CaV1.1: The atypical prototypical voltage-gated Ca2+ channel

Abstract

CaV1.1 is the prototype for the other nine known CaV channel isoforms, yet it has functional properties that make it truly atypical of this group. Specifically, CaV1.1 is expressed solely in skeletal muscle where it serves multiple purposes; it is the voltage sensor for excitation-contraction (EC) coupling and it is an L-type Ca2+ channel which contributes to a form of activity-dependent Ca2+ entry that has been termed Excitation-Coupled Ca2+ Entry (ECCE). The ability of CaV1.1 to serve as voltage-sensor for EC coupling appears to be unique amongst CaV channels, whereas the physiological role of its more conventional function as a Ca2+ channel has been a matter of uncertainty for nearly 50 years. In this chapter, we discuss how CaV1.1 supports EC coupling, the possible relevance of Ca2+ entry through CaV1.1 and how alterations of CaV1.1 function can have pathophysiological consequences.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…The direct Ca V 1.1-RyR1 conformational coupling has been shown to involve the Ca V 1.1 a1-subunit II-III intracellular loop (Block et al, 1988;Nakai et al, 1998;Grabner et al, 1999). The Ca V 1.1 channel expressed in adult muscle conducts a very small amplitude, slow-activating Ca 2+ current with a very right-shifted voltage sensitivity, making this channel a truly atypical Ca 2+ channel (for review, see Bannister and Beam, 2013). Typical intramembrane charge movements (gating currents), voltage-gated SR Ca 2+ release, and tetrad formation can all be restored upon reexpression of Ca V 1.1 a1 subunits in Ca V 1.1 a1-deficient skeletal muscle myotubes (Tanabe et al, 1988;Takekura et al, 1994), demonstrating the essential role of Ca V 1.1 in skeletal muscle.…”

“…Voltage-gated calcium channels are required for key functions in excitable cells, including transmitter release and hormone secretion , excitation-transcription coupling (Wheeler et al, 2012), and excitation-contraction coupling (Bannister and Beam, 2013). To determine which calcium channels are involved in specific processes, we can employ a range of selective drugs as blockers of the different channels, as part of the armory of experimental tools.…”

Bridging the myoplasmic gap II: more recent advances in skeletal muscle excitation–contraction coupling

“…As the functional role(s) of each of the intracellular segments of the α 1S subunit have already been summarized in earlier reviews (Bannister, 2007;Bannister and Beam, 2013a), I will only discuss them briefly here. The relatively short α 1S amino terminus is dispensable for both EC coupling (Bannister and Beam, 2005) and channel function, while the α 1S III-IV loop influences EC coupling indirectly through its ability to regulate gating (Bannister et al, 2008).…”

Membrane depolarization increases ryanodine sensitivity to Ca2+ release to the cytosol in L6 skeletal muscle cells: Implications for excitation–contraction coupling

“…As is evident from Figure 4, under control conditions, a peak of inward current was evident at about 35 mV, as expected from previous studies. 23,24 However, the additional presence of ryanodine led to strong suppression of these currents. .................................................................................................................. by the prior addition of thapsigargin, i.e.…”