Review
TARPs differentially decorate AMPA receptors to specify neuropharmacology

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Transmembrane AMPA receptor regulatory proteins (TARPs) are the first identified auxiliary subunits for a neurotransmitter-gated ion channel. Although initial studies found that stargazin, the prototypical TARP, principally chaperones AMPA receptors, subsequent research demonstrated that it also regulates AMPA receptor kinetics and synaptic waveforms. Recent studies have identified a diverse collection of TARP isoforms – types Ia, Ib II – that distinctly regulate AMPA receptor trafficking, gating and neuropharmacology. These TARP isoforms are heterogeneously expressed in specific neuronal populations and can differentially sculpt synaptic transmission and plasticity. Whole-genome analyses also link multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorder. TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders.

Section snippets

Multiple mechanisms regulating AMPA receptor functions

Glutamate represents the primary excitatory neurotransmitter in the mammalian brain. The AMPA receptor subtype mediates most fast neurotransmission by serving as a glutamate-gated ion channel. In addition to initiating neuronal firing, AMPA receptors also underlie aspects of synaptic plasticity. Activity-dependent modification of AMPA receptor function mediates long-term changes in synaptic efficacy that underlie physiological phenomena such as learning and memory as well as pathological

Stargazin as the prototypical AMPAR auxiliary subunit

The discovery that transmembrane proteins can regulate AMPA receptors initially derived from a seemingly unrelated investigation – the analysis of stargazer mutant mice, which suffer from absence epilepsy and cerebellar ataxia [13]. Physiological studies of stargazer showed lack of functional AMPA receptors in cerebellar granule cells [14], even though cerebellar GluA subunit proteins occurred at nearly normal levels 14, 15. Molecular and cellular studies revealed that stargazing [16], the

Two subfamilies of Type I TARPs differentially control neuronal AMPA receptors

Following the original discovery of stargazin as an AMPA receptor auxiliary subunit, a family of three closely related TARPs were identified [26]. These four TARPs, stargazin (or γ-2) and γ-3, γ-4, γ-8, which show some homology with the γ-1 subunit of skeletal muscle voltage-dependent calcium channels, are heterogeneously expressed throughout the brain. For example, γ-8 is preferentially expressed in the hippocampus, and knockout of γ-8 selectively reduces AMPA receptor function and synaptic

Type II TARPs modulate gating of specific AMPA receptor subunits

Of the remaining γ subunits, Type I TARPs have a closer sequence resemblance to γ-5 and γ-7 than with γ-1, γ-6 and claudin proteins, which are not abundantly expressed in brain. Similar to Type I TARPs, γ-5 and γ-7 are selectively enriched in specific neuronal and glial cells, which suggest possible roles for γ-5 and γ-7 in regulating synaptic receptors [32]. Indeed, biochemical and physiological studies revealed association of γ-5 and γ-7 with neuronal AMPA receptors and showed that they

TARPs change the pharmacology of AMPA receptor partial agonists and antagonists

This broad array of distinct classes of TARP subunits provides a robust substrate for differential control of synaptic transmission. Indeed, recent studies have established crucial roles for TARPs in AMPA receptor pharmacology and physiology. TARPs modulate AMPA receptor responses both to endogenous ligands (glutamate and polyamines) and to pharmacological agents. Kainate and domoate are naturally occurring constrained glutamate analogs that evoke non-desensitizing responses from heterologously

The first extracellular loop in TARPs controls channel gating

Molecular dissection of TARPs has begun to elucidate the domains that mediate differential regulation of AMPA receptor trafficking and function. TARPs comprise four transmembrane domains oriented such that both the N- and C-termini reside within the cell (Figure 2). The first, larger extracellular domain (EX1) of TARPs dictates their effects on AMPA receptor pharmacology and gating. However, alignment of the EX1 domains of TARPs shows important differences between Type Ia, Type Ib and Type II

Possible roles for TARPs in human epilepsies

AMPA receptors play a central role in numerous neurological and psychiatric disorders. The discovery of TARPs provides additional pathological avenues for investigation within CNS disorders involving excitatory transmission, including epilepsy. One form of epilepsy, absence epilepsy, typically arises from abnormally synchronized activity of the cortex and thalamus. In several mice strains, mutation of calcium channels to modulate their function produces absence epilepsy in addition to other

Concluding remarks

TARPs represent the first recognized auxiliary subunit for a ligand-gated ion channel. Discovery and characterization of a TARP family serve as keys for uncovering molecular mechanisms that control synaptic transmission in specific neuronal pathways. Despite the rapid progress in understanding of TARPs and their actions on AMPA receptors, many questions remain (Box 1). In addition, cornichon proteins have also been identified as auxiliary subunits for AMPA receptors that lack TARPs [69]. Other

Acknowledgements

The authors thank Drs. Roger Nicoll (UCSF School of Medicine) and Susumu Tomita (Yale School of Medicine) for their critical reviews of this manuscript. All authors are full-time employees of Eli Lilly and Company.

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