A family of γ‐like calcium channel subunits

Klugbauer, Norbert; Dai, Shuiping; Specht, Verena; Lacinová, Ľubica; Marais, Elsé; Bohn, Georg; Hofmann, Franz

doi:10.1016/s0014-5793(00)01306-5

Cited by 165 publications

(142 citation statements)

References 24 publications

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“…The related isoforms, ␥ 3 and ␥ 4 , have been reported to have no effect on Ca v 3.3 currents (145). In contrast, ␥ 2 , ␥ 4 , and ␥ 5 have been reported to accelerate inactivation of Ca v 3.1 currents and shift steady-state inactivation by Ϫ4 mV (210). To reiterate, the electrophysiological activity of T-type ␣ 1 -subunits expressed alone is very similar to that observed with native channels.…”

Section: E Auxiliary Subunits?mentioning

confidence: 86%

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

Perez‐Reyes

2003

Physiological Reviews

1,488

1,442

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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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Section: E Auxiliary Subunits?mentioning

confidence: 86%

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

Perez‐Reyes

2003

Physiological Reviews

1,488

1,442

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“…In the recent past, a number of ␥ subunits that are expressed in a variety of tissues have been cloned (13)(14)(15)(16), and their functional roles are only beginning to be revealed. In general, the ␥ subunits appear to be inhibitory (7,22,30,34).…”

Section: Discussionmentioning

confidence: 99%

γ1 Subunit Interactions within the Skeletal Muscle L-type Voltage-gated Calcium Channels

Arikkath

Chen

Ahern

et al. 2003

Journal of Biological Chemistry

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Voltage-gated calcium channels mediate excitationcontraction coupling in the skeletal muscle. Their molecular composition, similar to neuronal channels, includes the pore-forming ␣ 1 and auxiliary ␣ 2 ␦, ␤, and ␥ subunits. The ␥ subunits are the least characterized, and their subunit interactions are unclear. The physiological importance of the neuronal ␥ is emphasized by epileptic stargazer mice that lack ␥ 2 . In this study, we examined the molecular basis of interaction between skeletal ␥ 1 and the calcium channel. Our data show that the ␣ 1 1.1, ␤ 1a , and ␣ 2 ␦ subunits are still associated in ␥ 1 null mice. Reexpression of ␥ 1 and ␥ 2 showed that ␥ 1 , but not ␥ 2 , incorporates into ␥ 1 null channels. By using chimeric constructs, we demonstrate that the first half of the ␥ 1 subunit, including the first two transmembrane domains, is important for subunit interaction. Interestingly, this chimera also restores calcium conductance in ␥ 1 null myotubes, indicating that the domain mediates both subunit interaction and current modulation. To determine the subunit of the channel that interacts with ␥ 1 , we examined the channel in muscular dysgenesis mice. Cosedimentation experiments showed that ␥ 1 and ␣ 2 ␦ are not associated. Moreover, ␣ 1 1.1 and ␥ 1 subunits form a complex in transiently transfected cells, indicating direct interaction between the ␥ 1 and ␣ 1 1.1 subunits. Our data demonstrate that the first half of ␥ 1 subunit is required for association with the channel through ␣ 1 1.1. Because subunit interactions are conserved, these studies have broad implications for ␥ heterogeneity, function and subunit association with voltage-gated calcium channels.The L-type voltage-gated calcium channels of the skeletal muscle serve both as a voltage-gated calcium channel and as a voltage sensor for excitation-contraction (EC) 1 coupling (1, 2). These channels serve to couple depolarization to intracellular calcium release via the ryanodine receptor. The sites of EC coupling in the skeletal muscle are the triads, which are highly organized junctions comprising the t-tubules and the underlying sarcoplasmic reticulum (3). The voltage-gated calcium channels are localized predominantly in the t-tubules in close association with the ryanodine receptor in the sarcoplasmic reticulum (4, 5).At the molecular level, the calcium channel is composed of the pore-forming ␣ 1 1.1 subunit and auxiliary ␣ 2 ␦, ␤ 1 , and ␥ 1 subunits (6). This four-subunit composition of the channels is similar to that of the neuronal voltage-gated channels (7, 8). The auxiliary ␣ 2 ␦ and ␤ subunits enhance membrane trafficking of the ␣ 1 1.1 subunit and modulate the voltage-dependent kinetics of the channel (9). In addition to the role of the ␤ 1 subunit in the trafficking of the channel, it also has a crucial role in EC coupling as emphasized by the absence of EC coupling and early lethality in mice that lack the skeletal ␤ 1 subunit (10). The subunit interactions of the ␣ 2 ␦ and ␤ subunits have been relatively well defined.The ␥ 1 subunit is ...

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“…In addition to the four identified TARPs, the mammalian genome contains several additional genes related to stargazin (Klugbauer et al, 2000;Burgess et al, 2001;Chu et al, 2001) that were named based on their similarity to the ␥-1 calcium channel subunit from skeletal muscle. As opposed to the well studied TARPs (␥-2, ␥-3, ␥-4, ␥-8), much less is known of the other homologous genes, ␥-5, ␥-6, and ␥-7.…”

Section: Introductionmentioning

confidence: 99%

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

Kato¹,

Zhou²,

Milstein³

et al. 2007

J. Neurosci.

125

168

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AMPA-type glutamate receptors (GluRs) mediate most excitatory signaling in the brain and are composed of GluR principal subunits and transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits. Previous studies identified four mammalian TARPs, ␥-2 (or stargazin), ␥-3, ␥-4, and ␥-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous ␥-5 and ␥-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of ␥-5 and ␥-7 in the cerebellum, where ␥-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar ␥-7 avidly and selectively binds to AMPA receptor GluR subunits and also binds to the AMPA receptor clustering protein, postsynaptic density-95 (PSD-95). Furthermore, ␥-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, ␥-7 but not ␥-5 greatly enhances AMPA receptor glutamateevoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of ␥-7 but not ␥-5 increases AMPA receptor-mediated currents. Compared with stargazin, ␥-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define ␥-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.

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A family of γ‐like calcium channel subunits

Cited by 165 publications

References 24 publications

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

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

γ1 Subunit Interactions within the Skeletal Muscle L-type Voltage-gated Calcium Channels

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

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