Subunits of Voltage-Gated Calcium Channels

Dolphin, Annette C.

doi:10.1023/b:jobb.0000008026.37790.5a

Cited by 384 publications

(396 citation statements)

References 168 publications

(289 reference statements)

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“…So, how does the lack of the ␤ 1a protein affect expression and function of the DHPR in skeletal muscle? Based on extensive coexpression experiments in heterologous systems (31,32) and on results from the ␤ 1a -null mouse (8,11), a lack of ␣ 1S triad expression would have been expected. However, immunofluorescence analysis of the fully differentiated zebrafish myotubes clearly demonstrated that ␤ 1a deficient cells are able to correctly target ␣ 1S into the triads (Fig.…”

Section: ) Statistical Significance Was Determined By Using the ⌬Cmentioning

confidence: 99%

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Schredelseker

Biase

Obermair

et al. 2005

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

137

164

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Homozygous zebrafish of the mutant relaxed (red ts25 ) are paralyzed and die within days after hatching. A significant reduction of intramembrane charge movements and the lack of depolarizationinduced but not caffeine-induced Ca 2؉ transients suggested a defect in the skeletal muscle dihydropyridine receptor (DHPR). Sequencing of DHPR cDNAs indicated that the ␣1S subunit is normal, whereas the ␤1a subunit harbors a single point mutation resulting in a premature stop. Quantitative RT-PCR revealed that the mutated gene is transcribed, but Western blot analysis and immunocytochemistry demonstrated the complete loss of the ␤1a protein in mutant muscle. Thus, the immotile zebrafish relaxed is a ␤1a-null mutant. Interestingly, immunocytochemistry showed correct triad targeting of the ␣1S subunit in the absence of ␤1a. Freeze-fracture analysis of the DHPR clusters in relaxed myotubes revealed an Ϸ2-fold reduction in cluster size with a normal density of DHPR particles within the clusters. Most importantly, DHPR particles in the junctional membranes of the immotile zebrafish mutant relaxed entirely lacked the normal arrangement in arrays of tetrads. Thus, our data indicate that the lack of the ␤1a subunit does not prevent triad targeting of the DHPR ␣1S subunit but precludes the skeletal muscle-specific arrangement of DHPR particles opposite the ryanodine receptor (RyR1). This defect properly explains the complete deficiency of skeletal muscle excitationcontraction coupling in ␤1-null model organisms.calcium channels ͉ excitation-contraction coupling ͉ tetrads ͉ zebrafish E xcitation-contraction (EC) coupling is understood as the signal transduction process connecting membrane depolarization to the contraction of muscle cells. This process is initiated by the concerted action of two Ca 2ϩ channels, the plasmalemmal voltage-gated dihydropyridine receptor (DHPR) and the sarcoplasmic reticulum (SR) ryanodine receptor (RyR). In junctions of the SR with the plasma membrane (peripheral couplings) or with the transverse tubules (triads), membrane depolarization is sensed by the DHPR, which then triggers RyR opening and Ca 2ϩ release from the SR. In skeletal muscle cells, this signaltransduction is independent of Ca 2ϩ influx through the DHPR (1) but depends on protein-protein interaction between the DHPR and the RyR1 (2, 3). This physical coupling requires the coordinated arrangement of DHPRs and RyR1s in the junctions. In skeletal muscle triads and peripheral couplings, groups of four DHPRs (tetrads) are arranged in orthogonal arrays matching the opposing RyR1 arrays (4). Formation of DHPR tetrads requires the presence of RyR1.The skeletal muscle DHPR complex is composed of the voltage-sensing and pore-forming ␣ 1S subunit and the auxiliary subunits ␤ 1a , ␣ 2 ␦-1, and ␥ (5). Targeted deletions of the ␣ 2 ␦-1 and ␥ subunits do not critically interfere with EC coupling function (6, 7). In contrast, ␣ 1S and ␤ 1a subunit null-mutant mice display a lack of EC coupling and, thus, lethal muscle paralysis (8, 9). Although failure o...

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Section: ) Statistical Significance Was Determined By Using the ⌬Cmentioning

confidence: 99%

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Schredelseker

Biase

Obermair

et al. 2005

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

137

164

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“…To direct the signal to a specific subset of an extensive family of effectors, cells are endowed with a complex network of regulators that constrain the timing and spreading of the calcium increase. The subset of voltage-dependent calcium channels that are activated by strong depolarization, also called high voltage-activated (HVA) 3 channels, are heteromultimers consisting of a central pore-forming subunit (Ca V ␣ 1 ) that associates with one or more accessory subunits. Among them the accessory ␤-subunit (Ca V ␤) has traditionally been recognized as one of the most important modulator of HVA channels (1)(2)(3).…”

mentioning

confidence: 99%

“…The subset of voltage-dependent calcium channels that are activated by strong depolarization, also called high voltage-activated (HVA) 3 channels, are heteromultimers consisting of a central pore-forming subunit (Ca V ␣ 1 ) that associates with one or more accessory subunits. Among them the accessory ␤-subunit (Ca V ␤) has traditionally been recognized as one of the most important modulator of HVA channels (1)(2)(3). More recently, it has been shown that the same subunit mediates several other cellular processes (for review, see Ref.…”

mentioning

confidence: 99%

Homodimerization of the Src Homology 3 Domain of the Calcium Channel β-Subunit Drives Dynamin-dependent Endocytosis

Miranda-Laferte

González-Gutiérrez

Schmidt

et al. 2011

Journal of Biological Chemistry

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Voltage-dependent calcium channels constitute the main entry pathway for calcium into excitable cells. They are heteromultimers formed by an ␣ 1 pore-forming subunit (Ca V ␣ 1 ) and accessory subunits. To achieve a precise coordination of calcium signals, the expression and activity of these channels is tightly controlled. The accessory ␤-subunit (Ca V ␤), a membrane associated guanylate kinase containing one guanylate kinase (␤-GK) and one Src homology 3 (␤-SH3) domain, has antagonistic effects on calcium currents by regulating different aspects of channel function. Although ␤-GK binds to a conserved site within the ␣ 1 -pore-forming subunit and facilitates channel opening, ␤-SH3 binds to dynamin and promotes endocytosis. Here, we investigated the molecular switch underlying the functional duality of this modular protein. We show that ␤-SH3 homodimerizes through a single disulfide bond. Substitution of the only cysteine residue abolishes dimerization and impairs internalization of L-type Ca V 1.2 channels expressed in Xenopus oocytes while preserving dynamin binding. Covalent linkage of the ␤-SH3 dimerization-deficient mutant yields a concatamer that binds to dynamin and restores endocytosis. Moreover, using FRET analysis, we show in living cells that Ca V ␤ form oligomers and that this interaction is reduced by Ca V ␣ 1 . Association of Ca V ␤ with a polypeptide encoding the binding motif in Ca V ␣ 1 inhibited endocytosis. Together, these findings reveal that ␤-SH3 dimerization is crucial for endocytosis and suggest that channel activation and internalization are two mutually exclusive functions of Ca V ␤. We propose that a change in the oligomeric state of Ca V ␤ is the functional switch between channel activator and channel internalizer.Voltage-dependent calcium channels link membrane depolarization to transient increases in cytosolic calcium concentration, which in turn mediate a variety of cellular processes, including gene expression, contraction, neurotransmission, and exocytosis (1). To direct the signal to a specific subset of an extensive family of effectors, cells are endowed with a complex network of regulators that constrain the timing and spreading of the calcium increase. The subset of voltage-dependent calcium channels that are activated by strong depolarization, also called high voltage-activated (HVA) 3 channels, are heteromultimers consisting of a central pore-forming subunit (Ca V ␣ 1 ) that associates with one or more accessory subunits. Among them the accessory ␤-subunit (Ca V ␤) has traditionally been recognized as one of the most important modulator of HVA channels (1-3). More recently, it has been shown that the same subunit mediates several other cellular processes (for review, see Ref. 4), including regulation of insulin secretion (5), gene transcription (6) and endocytosis (7). Four Ca V ␤ isoforms (Ca V ␤ 1 to Ca V ␤ 4 ) have been cloned from different nonallelic genes. Crystallographic studies of three of these provided the molecular basis for its functional versatility by identify...

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“…Divergence of ␤ subunit sequences has permitted multiple modulatory functions of ␤ subunits, which act in a cell type and calcium channel-specific manner (6,7). However, the virtual structural invariance of the ␤ subunit core across divergent species and its resemblance to a membrane-associated guanylate kinase scaffolding molecule suggests that a primary role of the ␤ subunit may be to stabilize membrane protein complexes associated with high voltage-activated calcium channels.…”

Section: Lymnaea Neurons Express a Ca V ␤ Subunit-a Full-lengthmentioning

confidence: 99%

“…Like other types of high voltage-activated channels, Ca v 2 channels exist as macromolecular complexes of a pore-forming ␣ 1 subunit and ancillary ␤, ␣ 2 -␦, and possibly ␥ subunits (5). The mammalian brain expresses four different types of ␤ subunits that interact to differentially modulate ␣ 1 subunit function (6,7). The functional effects of ␤ subunit coexpression include changes in the voltage dependences and rates of activation and inactivation, plus an increase in current densities (8 -17).…”

mentioning

confidence: 99%

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

Spafford

Minnen

Larsen

et al. 2004

Journal of Biological Chemistry

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Calcium channel ␤ subunits are key modulators of calcium channel function and membrane targeting of the pore-forming ␣ 1 subunit. Here we show that an invertebrate (Lymnaea stagnalis) homolog of P/Q-and Ntype calcium channels (LCa v 2), although colocalized with ␤ subunits in synapses of mature neurons, is physically uncoupled from the ␤ subunits in the leading edge of growth cones of outgrowing neurons. Moreover, LCa v 2 channels that mediate transmitter release in mature synapses also participate in neuronal outgrowth in growth cones. The differential association of ␤ subunits with synaptic calcium channels and those expressed in emergent neuronal growth suggests that ␤ subunits may play a role in the transformation of Ca v 2 calcium channel function in immature neurons and mature synapses.

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Subunits of Voltage-Gated Calcium Channels

Cited by 384 publications

References 168 publications

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Homodimerization of the Src Homology 3 Domain of the Calcium Channel β-Subunit Drives Dynamin-dependent Endocytosis

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

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Subunits of Voltage-Gated Calcium Channels

Cited by 384 publications

References 168 publications

The β 1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

The β 1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Homodimerization of the Src Homology 3 Domain of the Calcium Channel β-Subunit Drives Dynamin-dependent Endocytosis

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

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The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle