Kainate receptor trafficking: physiological roles and molecular mechanisms

Pharmacology & Therapeutics 104 (2004) 163–172

www.elsevier.com/locate/pharmthera

Kainate receptor trafficking: physiological roles and

molecular mechanisms

John T.R. Isaaca,b,*, Jack Mellorb, David Hurtadoa, Katherine W. Rochea

aNational Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3701, USAbMRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol BS8 1TD, UK

Abstract

Recently, there has been intense interest in the mechanisms regulating the trafficking and synaptic targeting of kainate receptors in

neurons. This topic is still in its infancy when compared with studies of trafficking of other ionotropic glutamate receptors; however, it is

already clear that mechanisms exist for subunit- and splice variant-specific trafficking of kainate receptors. There is also enormous diversity

of kainate receptor targeting, with the best-studied neurons in this regard being hippocampal CA3 pyramidal neurons and CA1 GABAergic

interneurons. This review summarizes the current state of knowledge on this topic, focusing on the molecular mechanisms of kainate receptor

trafficking and the potential for these mechanisms to regulate neuronal kainate receptor function.

D 2004 Elsevier Inc. All rights reserved.

Keywords: Kainate receptor; Glutamate; Hippocampus; ER retention motif; Receptor targeting; Synaptic plasticity

Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; A/C, associational commissural; Eph, ephrin; EPSC, excitatory postsynaptic

current; ER, endoplasmic reticulum; GFP, green flourescent protein; GRIP, glutamate receptor interacting protein; IPSC, inhibitory postsynaptic current;

NMDA, N-methyl-D-aspartate; PDZ, postsynaptic density 95/disc large/zonula occludens-1; PICK: protein interacting with C-kinase 1; PM, plasma

membrane; PSD-95/SAP90, postsynaptic density protein-95/synapse associated protein 90; TM, transmembrane.

0163-7258/$ - see f

doi:10.1016/j.pharm

* Correspondin

E-mail address:

Contents

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isa

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

2. Diverse locations and functions of kainate receptors in the hippocampus . . . . . . . . 164

3. Kainate receptors in CA3 pyramidal neurons. . . . . . . . . . . . . . . . . . . . . . . 165

3.1. Postsynaptic kainate receptors in CA3 pyramidal cells . . . . . . . . . . . . . . 165

3.2. Presynaptic kainate receptors in CA3 pyramidal neurons . . . . . . . . . . . . . 166

4. CA1 interneurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

4.1. Somatodendritic kainate receptors in CA1 interneurons. . . . . . . . . . . . . . 166

4.2. Presynaptic kainate receptors in CA1 interneurons . . . . . . . . . . . . . . . . 167

5. Kainate receptor targeting in neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . 167

6. Molecular mechanisms regulating kainate receptor expression at the synapse . . . . . . 168

6.1. Kainate receptors en route to the plasma membrane . . . . . . . . . . . . . . . 168

6.2. Beyond the C-terminus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

6.3. Kainate receptor binding proteins and synaptic targeting . . . . . . . . . . . . . 170

t matter D 2004 Elsevier Inc. All rights reserved.

ra.2004.08.006

thor. Tel.: 44 117 928 7400; fax: 44 117 929 1687.

[email protected] (J.T.R. Isaac).

J.T.R. Isaac et al. / Pharmacology & Therapeutics 104 (2004) 163–172164

7. Conclusions and prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Table 1

mRNA expression levels for kainate receptor subunits in neurons in the

hippocampal formation

Cell type GluR5 GluR6 GluR7 KA1 KA2

Dentate granule + +++ ++ +++ +++

CA3 pyramidal + +++ � +++ +++

CA3 interneuron +++ ++ ++ � �CA1 pyramidal � ++ � � ++

CA1 interneuron +++ ++ ++ � �For references, see accompanying text. Key: +++, high; ++, moderate; +,

low; �, not detected.

1. Introduction

Kainate receptors are 1 of the 3 ionotropic glutamate

receptor subtypes. They are widely expressed in the central

nervous system (Wisden & Seeburg, 1993; Bahn et al.,

1994; Bettler & Mulle, 1995), critically involved in

excitatory and inhibitory neurotransmission and the induc-

tion and expression of long-term potentiation, and heavily

implicated in diseases such as epilepsy (Frerking & Nicoll,

2000; Lerma et al., 2001). Kainate receptors are tetrameric

combinations of GluR5–7 and KA1–2 subunits (Wisden &

Seeburg, 1993; Bettler & Mulle, 1995). The GluR5–7

subunits are functional ion channels either as homomers or

in heteromeric combination with other GluR5–7 and KA1–2

subunits. The KA subunits are not thought to produce

functional homomeric channels (Ren et al., 2003a, 2003b)

and are thought to form part of heteromers in combination

with the GluR5–7 subunits.

Much more so than the other ionotropic glutamate

receptors (AMPA and N-methyl-d-aspartate [NMDA]),

kainate receptors are targeted to a variety of presynaptic

and postsynaptic locations often within the same neuron. At

these locations, they perform specific tasks related to the

regulation of presynaptic function (of glutamate trans-

mission and transmission mediated by other transmitters,

most notably GABA), postsynaptic neurotransmission, or

regulation of membrane excitability (Frerking & Nicoll,

2000; Kullmann, 2001; Lerma et al., 2001; Lerma, 2003).

Moreover, there is evidence that kainate receptors at

different locations have distinct subunit compositions and

in some cases, in addition to their classic ionotropic

function, may couple with G protein-dependent signaling

mechanisms (Rodriguez-Moreno & Lerma, 1998; Frerking

et al., 2001; Melyan et al., 2002; Rozas et al., 2003).

Furthermore, there is evidence that kainate receptor expres-

sion at synapses may be acutely regulated during long-term

synaptic plasticity (Kidd & Isaac, 1999) and during

development (Bahn et al., 1994; Kidd & Isaac, 1999; Kidd

et al., 2002). Thus, from a physiological point of view, the

trafficking and targeting mechanisms regulating kainate

receptor subunits are required to fulfill a variety of tasks.

This review will describe the recent advances in under-

standing kainate receptor trafficking and targeting mecha-

nisms in the context of the current understanding of the

diverse physiological functions of kainate receptors.

In situ hybridization studies show that mRNA for kainate

receptor subunits is highly expressed throughout the brain

and spinal cord (Wisden & Seeburg, 1993; Bahn et al.,

1994; Bettler & Mulle, 1995). However, due to a paucity of

high-quality subunit-selective antibodies, few studies of the

expression of kainate receptor subunits at the protein level

have been performed. Therefore, most information regard-

ing the localization of kainate receptors and specific

subunits in certain locations in neurons has been obtained

from functional studies combined with pharmacology and/

or the use of kainate receptor subunit-deficient mice. The

most detailed functional analysis of kainate receptors has

been performed on hippocampal circuits for both glutama-

tergic and GABAergic neurons. We will therefore use the

hippocampus as an example to illustrate the diverse

locations at which kainate receptors are found.

2. Diverse locations and functions

of kainate receptors in the hippocampus

In the hippocampus, mRNA for all kainate receptor

subunits is found, but expression levels differ greatly

between different regions and cell types (Table 1; Bahn et

al., 1994; Bureau et al., 1999; Paternain et al., 2000).

Principal cells of the CA3 region and dentate gyrus show

high levels of message for GluR6, KA2, and KA1 but low

levels for GluR5. GluR7 is found in dentate granule cells.

Interneurons in the CA3 region express high levels of GluR5

and populations also express GluR6 and GluR7. KA1–2

subunits have low levels of expression in CA3 interneurons.

In the CA1 region, principal cells generally show lower

levels of expression for kainate receptor subunits compared

with CA3 but have detectable levels of transcripts for GluR6

and KA2. A population of CA1 interneurons have high levels

of GluR5, and another potentially overlapping population

show high levels of GluR6. GluR7 is selectively expressed in

a population of stratum oriens interneurons. KA1–2 subunits

do not appear to be expressed in interneurons.

Thus, simply from the mRNA expression data, there is

potential for considerable cell type-specific differences in the

subunit combination of kainate receptor complexes. Because

mRNA data only provide information on the amount of new

protein synthesized, regional and cell-specific information at

Fig. 1. Locations of kainate receptors in hippocampal CA3 pyramidal neurons. For this and Fig. 2, subunit information is provided where there is positive

evidence for the presence of a particular subunit. See text for references and details.

J.T.R. Isaac et al. / Pharmacology & Therapeutics 104 (2004) 163–172 165

the protein level for the different kainate receptor subunits is

required to get a clear picture of exactly what subunits are

expressed and where. In the absence of such information,

however, functional studies using selective pharmacological

agents and kainate receptor subunit-deficient mouse strains

have provided most of the information on the location of

kainate receptors and their subunit compositions. A sum-

mary of kainate receptor locations and subunit information

where known is provided in Figs. 1 and 2.

3. Kainate receptors in CA3 pyramidal neurons

3.1. Postsynaptic kainate receptors in CA3 pyramidal cells

CA3 pyramidal cells differentially target kainate recep-

tors to postsynaptic locations. They are found postsynapti-

cally at mossy fiber synapses where they mediate a slow

synaptic current but remarkably not at associational

commissural (A/C) synapses also located on the apical

dendrites of the same neurons (Castillo et al., 1997; Vignes

& Collingridge, 1997). Evidence from electrophysiological

studies suggests that postsynaptic kainate receptors are

located at the postsynaptic density. This is based on studies

on mossy fiber–CA3 synapses and in other brain areas

Fig. 2. Locations of kainate receptors in hippocampal GABAerg

showing a lack of effect on the size and kinetics of the

kainate receptor-mediated excitatory postsynaptic current

(EPSC) for manipulations that modulate glutamate clear-

ance from the synaptic cleft (Castillo et al., 1997; Vignes &

Collingridge, 1997; Bureau et al., 2000; Kidd & Isaac,

2001; but see Min et al., 1998). In addition, studies using

biochemical techniques and/or immunogold localization of

kainate receptor subunits also support the view that kainate

receptors are located at the postsynaptic density (Darstein et

al., 2003; Hirbec et al., 2003).

Studies of kainate receptor subunit-deficient mice have

proven to be very informative in understanding the subunit

composition of specific functionally identified kainate

receptors. At mossy fiber synapses, such genetic manipu-

lations provide evidence for GluR6-containing receptors

mediating the kainate receptor-mediated EPSC (Mulle et al.,

1998). This is supported by pharmacological evidence

demonstrating a low sensitivity to GluR5 selective ligands

in CA3 pyramidal cells (Lauri et al., 2001a), indicating a lack

of the involvement of this subunit postsynaptically. More

recent studies also provide immunogold and biochemical

evidence for postsynaptic GluR6/KA2 heteromers (Darstein

et al., 2003) and a role for KA2 in determining the kinetics of

the kainate receptor-mediated EPSC (Contractor et al.,

2003). Thus, the current data all point to GluR6/KA2

ic CA1 interneurons. See text for references and details.


heteromers as the major postsynaptic kainate receptor

subunit composition at mossy fiber synapses.

3.2. Presynaptic kainate

receptors in CA3 pyramidal neurons

The A/C input onto CA3 pyramidal neurons, connections

between CA3 pyramidal neurons, is regulated by presy-

naptic kainate receptors. A/C synapses are negatively

regulated by kainate receptor agonists (Bortolotto et al.,

1999; Contractor et al., 2000; Lauri et al., 2001b), and

pharmacological studies primarily performed on rat tissue

indicate the involvement of GluR5-containing receptors

(Bortolotto et al., 1999; Lauri et al., 2001b). However,

controversy exists in this regard because genetic evidence in

mice points to a critical role for GluR6 subunits and

provides evidence against the involvement of GluR5

(Contractor et al., 2000). The reason for this discrepancy

is at present unclear but could suggest that GluR5

trafficking to synapses is impaired in the GluR6 knockout

or that kainate receptor stoichiometry is different in rats

compared with mice.

The postsynaptic effects of kainate receptor agonists, at

doses that cause strong inhibition of A/C transmission, are

unlikely to account for the presynaptic effects on trans-

mission (Vignes et al., 1998; Contractor et al., 2000). This

indicates that there is a population of presynaptic kainate

receptors located close to A/C terminals. In support of this

idea, the frequency of action potential independent mini-

ature EPSCs is increased by kainate receptor agonists

(Contractor et al., 2000; but see Castillo et al., 1997).

Puzzlingly, however, Contractor et al. (2000) reported that

the effect on miniature EPSC frequency was selectively lost

in GluR5 receptor subunit-deficient mice. This was despite

evidence provided in the same study against a selective role

of GluR5 in regulating evoked release at any glutamatergic

input onto CA3 pyramidal neurons. This apparent paradox

is still unresolved but could indicate that there is more than

1 presynaptic kainate receptor subtype. Thus, although

several unresolved issues concerning the exact location and

subunit identity of the presynaptic kainate receptor(s)

remain, the data suggest that CA3 pyramidal neurons target

GluR6 and GluR5 subunit containing kainate receptors to

A/C terminals. The possibility also exists for at least 2

different types of presynaptic kainate receptors of different

subunit composition being present.

Kainate receptors also regulate transmission at CA3-CA1

synapses, the Schaffer collateral/commissural input. This

has been studied in CA1 pyramidal neurons where kainate

receptor agonists are found to depress excitatory trans-

mission (Chittajallu et al., 1996; Kamiya & Ozawa, 1998;

Vignes et al., 1998; Bortolotto et al., 1999; Frerking et al.,

2001; Clarke & Collingridge, 2002). Pharmacological

evidence suggests that GluR5-containing receptors are

involved (Vignes et al., 1998; Bortolotto et al., 1999; Clarke

& Collingridge, 2002), although this issue has not been

addressed in kainate receptor subunit-deficient mice. The

evidence suggests that the presynaptic kainate receptor

directly regulates transmission at the terminal (Frerking et

al., 2001; Clarke & Collingridge, 2002) and that the

mechanism involves a novel metabotropic action of the

kainate receptor through a pertussis toxin-sensitive G

protein-mediated mechanism (Frerking et al., 2001).

Schaffer collateral/commissural axons also synapse onto

CA1 interneurons; however, to date, it has not been reported

if these synapses are also regulated by kainate receptors.

Overall, the available evidence indicates that CA3 pyrami-

dal neurons target kainate receptors to their terminals in the

CA1 region. These kainate receptors appear to contain

GluR5 subunits and also couple to a metabotropic cascade

involving a pertussis toxin-sensitive G protein. The degree

of similarity of these presynaptic kainate receptors to those

at A/C terminals in CA3 is not fully explored; therefore, it is

not clear if CA3 neurons target different kainate receptor

subtypes to distinct terminals.

4. CA1 interneurons

GABAergic interneurons in CA1 are a second cell type

for which there is considerable evidence that kainate

receptors of different subunit compositions can be targeted

to diverse locations. GABAergic interneurons are found

throughout the CA1 region of the hippocampus and can be

subdivided into many subtypes based on their anatomical,

neurochemical, and electrophysiological signature (Macca-

ferri & Lacaille, 2003). All CA1 interneuron subtypes

studied thus far exhibit functional kainate receptor-mediated

responses (Cossart et al., 1998). However, the majority of

the work on this topic does not distinguish between

interneuron subtype; therefore, the degree of intersubtype

variation in kainate receptor expression and function is not

well explored.

4.1. Somatodendritic kainate receptors in CA1 interneurons

Kainate receptors are found postsynaptically at glutama-

tergic synapses on CA1 interneurons where they mediate a

slow EPSC (Cossart et al., 1998; Frerking et al., 1998).

Pharmacological evidence suggests that these receptors

contain GluR5 subunits (Cossart et al., 1998), although

genetic investigation of the subunit composition of these

synaptic receptors has yet to be reported.

There is considerable controversy concerning the mech-

anism(s) by which kainate receptors regulate GABAergic

interneuron function (Kullmann, 2001). However, it is

generally agreed that kainate receptors located on somato-

dendritic membranes mediate the intense excitation that is

induced in interneurons by kainate receptor agonists

(Rodriguez-Moreno et al., 1997, 2000; Cossart et al.,

1998; Frerking et al., 1998, 1999; Rodriguez-Moreno &

Lerma, 1998; Bureau et al., 1999; Mulle et al., 2000).


Activation of these receptors causes a profound increase in

the frequency of spontaneous (action potential-dependent)

inhibitory postsynaptic currents (sIPSCs) recorded in CA1

pyramidal cells and interneurons. It is not clear if these

somatodendritic receptors are the same population as those

present at glutamatergic synapses or if they are an additional

or overlapping population. Pharmacological evidence indi-

cates that these receptors contain GluR5 subunits (Cossart et

al., 1998; Rodriguez-Moreno et al., 2000), and genetic

studies indicate that most are GluR5/6 heteromers (Bureau

et al., 1999; Mulle et al., 2000).

4.2. Presynaptic kainate receptors in CA1 interneurons

It is also generally agreed that kainate receptor agonists

cause a depression of evoked IPSCs recorded in CA1

pyramidal neurons (Clarke et al., 1997; Rodriguez-Moreno

et al., 1997, 2000; Rodriguez-Moreno & Lerma, 1998;

Bureau et al., 1999; Frerking et al., 1999; Min et al., 1999;

Mulle et al., 2000). However, the mechanism for this is

controversial. One possibility is that there is a distinct

population of kainate receptors located presynaptically at

GABAergic terminals onto pyramidal neurons, which

inhibit GABA release. Evidence for this has been provided

in studies investigating the effects of kainate receptor

agonists on mIPSCs (Rodriguez-Moreno & Lerma, 1998;

Rodriguez-Moreno et al., 2000) and differential dose-

dependent effects of different agonists on somatodendritic

excitation and evoked IPSC depression (Rodriguez-Moreno

et al., 2000). These studies suggest that receptors at the

terminal have a different makeup from the somatodendritic

receptors in that they do not contain GluR5 (Rodriguez-

Moreno et al., 2000). However, there is also pharmaco-

logical and genetic evidence that much of the depression is a

consequence of the intense excitation by somatodendritic

receptors (Frerking et al., 1999; Mulle et al., 2000) and that

additional axonal and postsynaptic mechanisms also con-

tribute (Frerking et al., 1999; Kang et al., 2004). One final

twist to this debate has come from a more recent study

(Jiang et al., 2001), providing evidence for a kainate

receptor located close to the synaptic terminal for which

the physiological mode of action is to facilitate GABA

release rather than depress it as suggested previously.

Resolution of this debate is required for it to become clear

if CA1 interneurons do indeed target kainate receptors of a

specific subunit composition to terminals onto pyramidal

cells in addition to GluR5/6 receptors at somatodendritic

locations.

There is also evidence that CA1 interneurons can target

kainate receptors to axons and presynaptic terminals

contacting other interneurons (Mulle et al., 2000; Cossart

et al., 2001; Semyanov & Kullmann, 2001). Pharmaco-

logical activation of these presynaptic kainate receptors

decreases mIPSC frequency and evidence suggests that this

is GluR6 dependent with no involvement of GluR5 (Mulle

et al., 2000; Cossart et al., 2001). In addition, pharmaco-

logical or synaptic activation of kainate receptors causes a

direct depolarization of axons between interneurons result-

ing in increased excitability (Semyanov & Kullmann,

2001), although the subunit composition of these receptors

remains to be explored. This raises the possibility that

interneurons target kainate receptors to both terminals and

axons; however, it is still unclear whether they can select

between interneuron-interneuron and interneuron-pyrami-

dal cell connections. A simple scheme would be that

interneurons target GluR5/6 heteromers somatodendriti-

cally (including the postsynaptic density) and GluR6-

containing (but GluR5-lacking) receptors to axons and

terminals.

One final point of interest for kainate receptors in CA1

interneurons is that there is evidence that they too can

couple to a G protein-mediated metabotropic cascade. The

depression of evoked IPSCs in CA1 pyramidal neurons is

blocked by pertussis toxin and protein kinase C inhibitors

(Rodriguez-Moreno & Lerma, 1998). This is very similar

to the mechanism reported at glutamatergic synapses onto

CA1 pyramidal cells (Frerking et al., 2001).

5. Kainate receptor targeting in neurons

CA3 pyramidal neurons and CA1 interneurons provide

excellent illustrations of the complexity of kainate receptor

targeting. Although these 2 cell types are best characterized

in this regard, it is clear that kainate receptors are found in

presynaptic and postsynaptic locations in many other cell

types in the mammalian brain (Lerma et al., 2001). This

suggests that selective, subunit-specific targeting of kainate

receptors in neurons is a general principle. Considerable

controversy remains, even in the well-studied cell types, as

to exactly where kainate receptors are found. This is

primarily due to the reliance on electrophysiological data,

which can be ambiguous in its interpretation. Systematic

immunolocalization studies in native brain samples will be

required to fully elucidate the precise locations of kainate

receptors in neurons. In addition, there is the intriguing

finding that kainate receptors can couple to G protein-

dependent metabotropic cascades. This has been reported

for presynaptic receptors regulating GABAergic synapses

onto CA1 pyramidal neurons (Rodriguez-Moreno & Lerma,

1998), for presynaptic and postsynaptic receptors at

glutamatergic synapses onto CA1 pyramidal neurons

(Frerking et al., 2001; Melyan et al., 2002, 2004), and for

postsynaptic receptors in dorsal root ganglion cells (Rozas

et al., 2003). Consistently, this mechanism involves a

pertussis toxin-sensitive G protein and protein kinase C. It

would of great interest to understand the molecular

mechanisms by which these ionotropic receptors can couple

directly to a G protein and whether this coupling is subunit

specific. Clues to this may be provided by understanding

the trafficking and targeting mechanisms of kainate receptor

subunits.

Fig. 4. Tac kainate receptor chimeras used to identify C-terminal motifs that

regulate trafficking through the secretory pathway. A schematic depicts the

structure of Tac kainate receptor chimeras described in several recent

publications. The subcellular localization of each of these constructs is

listed. References for each of these findings are included.


6. Molecular mechanisms regulating

kainate receptor expression at the synapse

6.1. Kainate receptors en route to the plasma membrane

Following the cloning and identification of kainate

receptors, the initial studies characterizing the individual

subunits revealed important unique characteristics. Each

kainate receptor subunit confers distinct properties on

kainate receptors and additional diversity arises from both

alternative splicing (Fig. 3) and RNA editing of some of the

subunits. Whereas GluR5–7 can all form functional homo-

meric channels, the kainate receptor subunits KA1–2 cannot.

However, KA1–2 are capable of forming functional hetero-

meric channels with GluR5–7. These early studies on the

newly identified kainate receptor subunits did not provide

any insight as to why some of the subunits formed functional

homomeric channels but others did not. Only recently have

several independent groups begun to specifically probe the

oligomerization, trafficking, and synaptic targeting of the

individual kainate receptor subunits. This has led to the

identification of distinct motifs encoded within particular

subunits that control kainate receptor trafficking through the

secretory pathway and expression at synaptic sites. There are

subunit-specific and splice variant-specific motifs that

differentially regulate receptor targeting to the plasma

membrane (PM). In addition, cytosolic proteins have been

identified that regulate synaptic expression, all contributing

to a complex set of determinants regulating kainate receptor

expression at excitatory synapses.

Several studies aimed at identifying the molecular

mechanisms underlying kainate receptor trafficking have

focused on the KA2 subunit. Although it has long been

known that KA2 does not form functional homomeric

Fig. 3. GluR5 and GluR6 C-terminal splice variants. (A) Diagram depicting the G

domain (TM4) through the entire C-terminus. Conserved domains are depicted with

and GluR6 splice variants through the pertinent C-terminal regions. Accession n

(Z11712), GluR5-b (Z11713), and GluR5-c (Z11714). Accession numbers for the h

and GluR6-b (AJ301610).

channels, it was not clear if KA2 subunits could oligomerize

or reach the PM without assembly with additional kainate

receptor subunits. Recently, it was demonstrated that KA2

indeed forms homomeric complexes in heterologous cells

(Ren et al., 2003a), but it was also demonstrated that

homomeric KA2 is retained in the endoplasmic reticulum

(ER) unless coassembled with other kainate receptor

subunits such as GluR5–7 (Gallyas et al., 2003; Hayes et

al., 2003; Ren et al., 2003a). Using the Tac protein as a

reporter molecule for PM expression (Fig. 4), chimeric

analyses were performed to identify trafficking motifs

encoded within cytosolic regions of KA2. Experiments

evaluating the KA2 C-terminus using the TacKA2 chimeric

protein revealed that the KA2 C-terminus contained a

dominant ER retention motif (Hayes et al., 2003; Ren et

al., 2003a) consisting of a positively charged stretch of

amino acids, RRRRR (Fig. 5; Ren et al., 2003a). Using

TacKA2, it was further demonstrated that disruption of this

luR5 and GluR6 C-terminal splice variants from the fourth transmembrane

identical patterns. (B) Alignment of the amino acid sequences of the GluR5

umbers for the rat GluR5 splice variants depicted are as follows: GluR5-a

uman GluR6 splice variants depicted are as follows: GluR6-a (NM021956)

Fig. 5. Schematic of kainate receptor C-termini depicting the location of

defined motifs that regulate trafficking through the secretory pathway. The

positively charged motifs within GluR5 and KA2 regulate ER retention,

whereas the positively charged motif in GluR6 regulates egress from the ER.


stretch of 5 arginines abolished ER retention. Surprisingly,

PM expression of TacKA2 was still quite low, and

additional mutations revealed a putative C-terminal di-

leucine endocytic motif that mediated the rapid endocytosis

and low steady-state PM expression of TacKA2 even

following mutations of the ER retention motif. The

disruption of both the ER retention motif and the putative

endocytic motif increased PM expression of TacKA2;

however, the same mutations in full-length KA2 did not

yield functional homomeric channels (Ren et al., 2003a).

Thus, for KA2, both egress from the ER and the formation

of functional kainate receptors depend on heterooligomeri-

zation with other kainate receptor subunits (Gallyas et al.,

2003; Hayes et al., 2003; Ren et al., 2003a).

Using similar approaches, additional studies have now

defined trafficking motifs that regulate PM expression of

both GluR5 and GluR6 (Ren et al., 2003b; Jaskolski et al.,

2004; Yan et al., 2004). Unlike KA2, GluR6 is known to

form functional homomeric channels. However, in a recent

study, GluR6 was also demonstrated to have trafficking

information encoded within its C-terminus (Yan et al.,

2004). Systematic analysis of the GluR6 C-terminus using

truncation analyses of a GFP-tagged GluR6 subunit

revealed that a region between amino acids 868 and 880

was critical for GluR6 egress from the ER. Further site-

directed mutagenesis led to the identification of a positively

charged stretch of amino acids, CQRRLKH, that is essential

for efficient PM expression of GluR6 (Fig. 5). Disruption of

this motif using site-directed mutagenesis results in the ER

retention of a TacGluR6 chimera (Fig. 4), and similar

mutations in full-length GluR6 resulted in the reduction of

functional homomeric GluR6 channels expressed on the

PM. Interestingly, GluR6, which contains point mutations

within the CQRRLKH motif causing it to be ER retained,

still traffics to the PM when coexpressed with wild-type

GluR6 or KA2. Therefore, the GluR6 egress motif is not

essential, and oligomerization ultimately controls PM

expression. Jaskolski et al. also tested the possibility that

the PDZ-binding domain on GluR6 (-ETMA) described

previously (Garcia et al., 1998) could promote PM

expression and actively relieve ER retention as has been

described previously for the NR1–3 splice variant of the

NR1 subunit of NMDA receptors (Standley et al., 2000;

Scott et al., 2001; Xia et al., 2001). However, unlike NR1–3,

mutations in the PDZ-binding domain played no role in PM

expression of GluR6 (Jaskolski et al., 2004).

GluR5, like GluR6, is capable of forming homomeric

channels and also of combining with KA1–2 to form

heteromeric channels. Also like GluR6, GluR5 has multiple

isoforms due to alternative splicing (Fig. 3) and mRNA

editing. Two new studies demonstrate that alternative

splicing of GluR5 plays a critical role in PM expression

(Ren et al., 2003b; Jaskolski et al., 2004). Although all GluR5

splice variants are predominantly retained in the ER

(Jaskolski et al., 2004), the GluR5-2c splice variant displays

particularly robust ER retention. Interestingly, the 29 amino

acid insert in GluR5-2c contains a RXR ER retention motif

similar to that described for KA2, NMDA receptors, and K+

channels (Fig. 5). When this RLR motif is mutated to ALA,

GluR5-2c traffics to the PM in both heterologous cells and

neurons (Jaskolski et al., 2004). In addition, positively

charged residues in GluR5-2b that are conserved with

GluR5-2c have also been demonstrated to regulate egress

from the ER (Fig. 5; Ren et al., 2003b). Using the TacGluR5-

2b construct, it was demonstrated that mutation of R896, as

well as R900 and K901, promotes surface expression in

heterologous cells and hippocampal neurons. Furthermore, as

described for GluR6 (Jaskolski et al., 2004), mutations in the

GluR5 C-terminal PDZ binding domain do not regulate PM

expression (Ren et al., 2003b). Therefore, for GluR5, GluR6,

and KA2, the C-terminus has been found to contain essential

cis-acting elements that regulate trafficking to the PM.

6.2. Beyond the C-terminus

Whereas these recent studies have conclusively demon-

strated that the C-termini of kainate receptors, like all

glutamate receptors, contain essential motifs for trafficking

to the PM and regulation of synaptic expression, it is also

likely that the smaller intracellular loops and the trans-

membrane domains contain information critical for oligo-

merization, PM expression, and synaptic targeting. Indeed,

oligomerization has been shown previously to be dependent

on the extracellular N-terminus and possibly the trans-

membrane regions of AMPA and NMDA receptors

(Leuschner & Hoch, 1999; Ayalon & Stern-Bach, 2001;

Meddows et al., 2001). In addition, the pore lining region,

TM2, of the AMPA receptor subunit GluR2 contains a

critical arginine residue that is determined by alternative

splicing (the Q/R site). This amino acid determines the

calcium permeability of GluR2-containing AMPA receptors.

A study characterizing the trafficking of GluR2 through the

secretory pathway has demonstrated that the Q/R site also


regulates the egress of GluR2 from the ER (Greger et al.,

2002) as well as the tetramerization of AMPA receptors

(Greger et al., 2003). Furthermore, metabotropic glutamate

receptors have important protein binding and trafficking

information encoded in their intracellular loops. For

example, the specific interactions with G proteins are via

the metabotropic glutamate receptor second and third

intracellular loops (reviewed in Conn & Pin, 1997).

Although no trafficking motifs have been described within

the smaller loops of the ionotropic glutamate receptors,

other neurotransmitter receptors have trafficking informa-

tion encoded in regions other than the C-termini (Boyd et

al., 2003; Tan et al., 2004).

6.3. Kainate receptor binding

proteins and synaptic targeting

In recent years, several glutamate receptor binding

proteins have been identified. Many of these proteins were

isolated with the help of a yeast 2-hybrid screen in which the

intracellular C-termini of individual glutamate receptor

subunits were used as bbaitQ in screens of yeast 2-hybrid

libraries. Whereas some of the identified binding proteins

are subtype specific or display unique binding to a particular

subunit of a glutamate receptor subtype, other binding

proteins are more promiscuous and interact with KA,

AMPA, and NMDA receptors. We will discuss several of

the kainate receptor binding proteins, which have been

characterized in recent years and have been implicated in the

trafficking and synaptic expression of kainate receptors (for

related reviews on the subject, see De La Rue & Henley,

2002; Collingridge & Isaac, 2003).

Like many glutamate receptors, kainate receptors contain

a PDZ-binding motif at their extreme C-terminus. Studies on

the prototypic PDZ domain-containing family of proteins

including PSD-95/SAP90 have demonstrated that these

proteins bind to kainate receptors, cluster them, and

modulate their desensitization (Garcia et al., 1998; Mehta

et al., 2001). In another study, 4 PDZ domain-containing

proteins were isolated that bind to kainate receptors, PSD-

95, GRIP, PICK1, and syntenin (Hirbec et al., 2003). None

of these proteins are specific for kainate receptors among the

ionotropic glutamate receptors, as they also interact with

AMPA receptor and in some cases NMDA receptors (Kim et

al., 1995; Kornau et al., 1995; Dong et al., 1997; Hirbec et

al., 2002). Although at first glance the kainate receptor

binding proteins appear to lack binding specificity, studies

demonstrate functionally distinct roles for these proteins in

regulating kainate and AMPA receptors. Using an approach

that takes advantage of fusion proteins of kainate receptor

C-termini or synthetic peptides that differentially disrupt

binding of kainate receptors to PSD-95, GRIP, PICK1, and

syntenin, Hirbec et al. described the differential regulation

of AMPA and kainate receptors at hippocampal mossy

fiber–CA3 synapses of the hippocampus. Infusion of

GluR5-2b C-terminal fusion proteins resulted in the loss

of kainate receptor-mediated synaptic currents without

affecting the AMPA component. Using fusion proteins with

specific point mutations in the GluR5-2b C-terminus or

peptides to compete off endogenous interactions with

kainate and AMPA receptors, they provide evidence that

interactions with GRIP decrease synaptic kainate receptor

function while simultaneously increasing AMPA receptor

function at synapses. In addition, blockade of PICK1

interactions caused a depression of the kainate receptor-

mediated EPSC but had no effect on the AMPA receptor-

mediated EPSC. Although some of these peptides have also

been reported to affect presynaptic release probability at

mossy fiber–CA3 synapses through a mechanism involving

GRIP-Eph receptor interactions (Contractor et al., 2002), the

simultaneous differential regulation of AMPA and kainate

receptor-mediated responses at the same population of

inputs cannot be explained by such a mechanism. Rather,

these data indicate distinct roles for PICK1 and GRIP in the

regulation of synaptic AMPA and kainate receptors.

Previously, these proteins have been shown to regulate

AMPA receptor function by regulating surface expression;

thus, this is also a likely mechanism for the regulation of

kainate receptors by these interactors. Overall, these studies

point to a complex interplay between synaptic scaffolding

proteins and the various glutamate receptors at the

postsynaptic density.

In addition to PDZ domain-containing proteins, kainate

receptors have also been shown to interact with cadherin/

catenin complexes (Coussen et al., 2002), specifically h-catenin. Although cadherins/catenins do not possess PDZ

domains, they are known to interact with the PDZ domain-

containing proteins CASK and PSD-95 (Perego et al.,

2000), thereby still implicating PDZ domain interactions in

kainate receptor trafficking and synaptic targeting. It is

intriguing that these findings demonstrate that the GluR6

PDZ ligand (-ETMA) at the extreme C-terminus is required

for the h-catenin interaction, yet the GluR6-h-catenininteraction is indirect and not dependent on PSD-95 or

CASK (Coussen et al., 2002). More work is required to

determine the precise molecular basis for the GluR6

association with cadherin/catenin complexes and to define

the PDZ domain-containing proteins that link these

proteins.

In addition to the kainate receptor binding proteins

characterized thus far, it is likely that additional components

of the intracellular trafficking machinery will eventually be

shown to interact with kainate receptors. The numerous

subunit- and splice variant-specific trafficking motifs that

have been identified in the past year (Fig. 5) most likely

mediate specific protein-protein interactions regulating

particular steps in the secretory pathway. As future research

reveals additional binding partners, we will undoubtedly

learn more about the mechanisms regulating the precise

targeting of kainate receptors to both presynaptic and

postsynaptic sites and the functional consequences of such

interactions.


7. Conclusions and prospects

A consistent theme in the study of kainate receptors is

that neurons clearly have the ability to traffic and target

kainate receptors differentially from the closely related

AMPA receptors that coexist in the same cells. Moreover,

neurons can target kainate receptors in a subunit specific

manner, so that receptor complexes of specific compositions

and functions can be located at numerous different locations

within the same cell. How this is achieved is at present

largely unknown. Trafficking studies of kainate receptors

are still in their infancy in comparison with the better-

studied ionotropic AMPA and NMDA glutamate receptor

subtypes. However, it is already evident that mechanisms

exist for the subunit- and splice variant-specific trafficking

of kainate receptors. The challenge is now on to further

elucidate these mechanisms and understand how such

processes can lead to the complex differential and regulated

targeting of kainate receptors within neurons.

Acknowledgments

Supported by the Wellcome Trust (J.M. and J.T.R.I.),

MRC (J.M. and J.T.R.I.), and NINDS/NIH (K.W.R., D.H.,

and J.T.R.I.).

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Kainate receptor trafficking: physiological roles and molecular mechanisms

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