Biochemical and Biophysical Evidence for γ2 Subunit Association with Neuronal Voltage-activated Ca2+Channels

Kang, Myoung-Goo; Chen, Chien‐Chang; Felix, Ricardo; Letts, Verity A.; Frankel, Wayne N.; Mori, Yasuo; Campbell, Kevin P.

doi:10.1074/jbc.m100787200

Cited by 112 publications

(123 citation statements)

References 31 publications

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“…These and rolling Nagoya mice (with a further mutation on Cacna1a but not showing absence seizures) show ataxia and a wide variety of other central nervous system changes. The stargazer mouse has a mutation in Cacng2 that alters the function of Ca v 2.1 and Ca v 2.2 77 and modifies the cell surface expression of AMPA receptors. 78 The mutation in the lethargic mouse interferes with the ␤ 4 subunit modulatory action on the ␣ 1 subunit Ca v 2.1 and Ca v 2.2 although some compensatory subunit insertions ("reshuffling") may occur.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…The ␥ 2 -protein is only 25% identical to skeletal muscle ␥ and may play different physiological roles. Immunoprecipitation studies have shown that ␥ 2 may be a subunit of both HVA Ca v 2.2 Ca 2ϩ channels and glutamate receptors of the AMPA class (74,190,366). Coexpression of ␥ 2 inhibits the expression of Ca v 2.1 and Ca v 2.2 channels in the presence of ␣ 2 ␦ 1 and has minor effects on their biophysical properties (190,346).…”

Section: E Auxiliary Subunits?mentioning

confidence: 99%

“…Immunoprecipitation studies have shown that ␥ 2 may be a subunit of both HVA Ca v 2.2 Ca 2ϩ channels and glutamate receptors of the AMPA class (74,190,366). Coexpression of ␥ 2 inhibits the expression of Ca v 2.1 and Ca v 2.2 channels in the presence of ␣ 2 ␦ 1 and has minor effects on their biophysical properties (190,346). In contrast, ␥ 2 had little effect on Ca v 3.3 expression, although it could slow the decay of the tail current (145).…”

Section: E Auxiliary Subunits?mentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,521

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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“…It has been suggested that the change of [Ca 2ϩ ] i in local environment regulates the binding of chaperone proteins to AMPA receptors or phosphorylation of AMPA receptors (1). Based on recent studies (5,8,(22)(23)(24) and biochemical data in this study (Fig. 2), PSD95 or Ca 2ϩ channel ␥ 2 subunits (stargazin) could be a candidate chaperon protein modulating AMPA receptor trafficking depending on the Ca 2ϩ influx through Ca 2ϩ channels.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the association of the ␥ subunits (␥ 2 and ␥ 3 ) with neuronal Ca 2ϩ channels has recently been established (5,6), which is similar to the association of ␥ 1 subunit with skeletal Ca 2ϩ channels (7). Interestingly, a role of the ␥ 2 subunits (stargazin) in the trafficking͞clustering of AMPA receptors has been reported (8)(9)(10)(11).…”

mentioning

confidence: 91%

A functional AMPA receptor–calcium channel complex in the postsynaptic membrane

Kang

Chen

Wakamori

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ca 2؉ channels play critical roles in the regulation of synaptic activity. In contrast to the well established function of voltageactivated Ca 2؉ channels in the presynaptic membrane for neurotransmitter release, some studies are just beginning to elucidate the functions of the Ca 2؉ channels in the postsynaptic membrane.In this study, we demonstrated the functional association of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors with the neuronal Ca 2؉ channels. A series of biochemical studies showed the specific association of Ca v2.1 (␣1A-class) and Ca v2.2 (␣1B-class) with AMPA receptors in the postsynaptic membrane. Our electrophysiological and Ca 2؉ imaging analyses of recombinant Ca v2.1 and AMPA receptors also showed functional coupling of the two channels. Considering the critical roles of postsynaptic intracellular concentration of Ca 2؉ ([Ca 2؉ ]i) increase and AMPA receptor trafficking for long-term potentiation (LTP) and long-term depression (LTD), the functional association of Ca 2؉ channels with the AMPA receptors may provide new insights into the mechanism of synaptic plasticity.voltage-activated Ca 2ϩ channel ͉ stargazin ͉ glutamate receptor ͉ synaptic plasticity ͉ postsynaptic density N eurotransmitter-mediated communication between a presynaptic and a postsynaptic membrane is a fundamental neurophysiological phenomenon. The precise organization and dynamic change of presynaptic and postsynaptic protein components underlies the physiological regulation of synaptic efficacy. The study of the organization and dynamics of synaptic proteins is the key to our understanding of synaptic plasticity, neuronal development, and some neurological disorders.The ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor is one of the major types of glutamate receptors (GluRs) mediating neurotransmission in the excitatory postsynaptic membrane. Activity-dependent trafficking of AMPA receptors in and out of the postsynaptic membrane is one of the key mechanisms for synaptic plasticity such as long-term potentiation (LTP) and long-term depression. Although recent studies have identified several postsynaptic proteins that interact with the AMPA receptor C terminus and are potentially involved in AMPA receptor trafficking, the precise mechanism for the modulation of AMPA receptors trafficking in the postsynaptic membrane is still not clear (1).Voltage-activated Ca 2ϩ channels function in many fundamental physiological processes, including neurotransmission, muscle contraction, intracellular signaling, hormone secretion, and development. The function of voltage-activated Ca 2ϩ channels (called Ca 2ϩ channels or Ca v hereafter) for neurotransmission in the presynaptic membrane has been intensively studied because the Ca 2ϩ channel is a key player in the coupling of electric and chemical signals in presynapses. In addition to the presynaptic function, postsynaptic function of Ca 2ϩ channels is beginning to be revealed through recent biophysical studies. Induction of hippocampal mossy fiber LTP ...

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Biochemical and Biophysical Evidence for γ2 Subunit Association with Neuronal Voltage-activated Ca2+Channels

Cited by 112 publications

References 31 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

A functional AMPA receptor–calcium channel complex in the postsynaptic membrane

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