The biochemistry and molecular biology of the dihydropyridine-sensitive calcium channel

Campbell, Kevin P.; Leung, Albert; Sharp, Alan H.

doi:10.1016/0166-2236(88)90193-2

Cited by 306 publications

(117 citation statements)

References 45 publications

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“…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).…”

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confidence: 87%

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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confidence: 87%

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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“…The slowly inactivating, dihydropyridine (DHP)-sensitive, L-type calcium channels from skeletal muscle and heart have been well characterized with respect to their biochemical and molecular characteristics. They are membrane-spanning proteins consisting of several transmembrane subunits (reviewed in [3,4]). The al subunit which binds organic Ca?+ channel blockers [5-71 can function as a calcium channel, since the al subunit cDNA isolated from skeletal and cardiac muscle can direct expression of functional Ca'+ channels [8,9].…”

Section: Introductionmentioning

confidence: 99%

Expression of dihydropyridine‐sensitive brain calcium channels in the rat central nervous system

et al. 1992

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WC have localized dihydropyridine (DHP)-sensitive calcium channels in rat brain by in situ hybridization and immunohistochemistry. The mRNA for the dihydropyridine-sensitive calcium channel al subunit (DHPR-B) is prominently tocalized in neuronal cells in the olfactory bulb, dentate gyrus, hippooampus, arcuate nucleus, paraventricular nucleus, vcntromcdial nucleus, cerebral cortex, superior colliculus and the cerebellar Purkinje cell layer. Strong expression of DHPR-B mRNA was also found in the pituitary and pincal glands. DHP-sensitive calcium channel 01 subunit distribution has also been examined immunohistochcmically with polyclonal antibodies raised agGnst synthetic pptides specific for the DHPR-B al subunit protein. The results from immunohistochemistry were in good aSmemcnt with those from in situ hybridization. Thus, qional distribution and localization of DHPR-B mRNA and rl subunit protein in rat brain suggest that this type of DHP-sensitive brain calcium cbanncl may play an important role in excitation-secretion coupling functions in the neuroendocrine system.

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“…The voltage-dependent L-type calcium channel is known to consist of multiple subunits, 12,13) each of which possesses specific functions. The main subunit α1c bears the basic function for acting as the L-type calcium channel, 14,15) while the auxiliary subunits cooperate with α1c to regulate the net function as the Ltype calcium channel, [13][14][15][16][17][18][19][20][21] and as a consequence, would play important roles like α1c.…”

Section: Discussionmentioning

confidence: 99%

“…However, the L-type calcium channel is not a single molecule, but is known to consist of multiple subunits 12,13) : the main subunit α1c and the auxiliary subunits α2δ, β2, β3. The main subunit α1c bears the basic function of the calcium channel.…”

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confidence: 99%

“…It possesses the voltage sensor, the binding site for pharmacological agents, the inactivation gate, and moreover, determines the ion selectivity. 14,15) The α2δ and β auxiliary subunits modify these functions, ie, increase the activation 12) and inactivation kinetics, 15,16) controlling the open probability 17,18) and stability of the channel on the cell membrane. 19,20) Bosed on this information a hypothesis can be proposed that the expression of each subunit might be changing differently during the progression of cardiac hypertrophy, which may lead to the controversial or stage-dependent changes of Ica.…”

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confidence: 99%

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Time- and Subunit-dependent Differential mRNA Expression of L-type Ca2+ Channel during Progression of Right Ventricular Hypertrophy.

et al. 2001

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SUMMARYTo clarify the molecular basis for changes in L-type calcium channel (VLCC) density in ventricular hypertrophy, we analyzed the mRNA expression of all the subunits including the main subunit α1c and auxiliary subunits (α2δ, β2 and β3) composing VLCC in rat right ventricular hypertrophy (RVH) induced by monocrotaline injection. To test the hypothesis that the expression of each subunit might change differently during progression of RVH, leading to an altered electrophysiologic outcome for VLCC, we investigated the ratio of the mRNA level of each auxiliary subunit to the main subunit. After monocrotaline injection, α1c mRNA showed a transient decrease on the 14th day and thereafter significantly increased to reach approximately 1.8 fold that of the control level on the 21st day. The auxiliary subunit α2δ mRNA showed a pattern similar to that of α1c.The β3 mRNA increased rapidly after monocrotaline injection and increased approximately 4.1 fold. On the other hand, β2 mRNA showed no significant changes. Accordingly, only the mRNA ratio of β3 to α1c showed a significant increase among the auxiliary subunits after the monocrotaline injection. The ratio increased to a maximum of approximately 5.7 fold on the 14th day and thereafter decreased. These results suggest that VLCC density may be modified not only by α1c but also by its auxiliary subunit expression in ventricular hypertrophy, and provide a clue for understanding the controversial electrophysiologic results on VLCC density in hypertrophied hearts. (Jpn Heart J 2001; 42: 617-625)

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The biochemistry and molecular biology of the dihydropyridine-sensitive calcium channel

Cited by 306 publications

References 45 publications

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

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

Expression of dihydropyridine‐sensitive brain calcium channels in the rat central nervous system

Time- and Subunit-dependent Differential mRNA Expression of L-type Ca2+ Channel during Progression of Right Ventricular Hypertrophy.

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