Voltage-gated calcium channels represent the sole mechanism converting electrical signals of excitable cells into cellular functions such as contraction, secretion and gene regulation. Specific voltage-sensing domains detect changes in membrane potential and control channel gating. Calcium ions entering through the channel function as second messengers regulating cell functions, with the exception of skeletal muscle, where CaV1.1 essentially does not function as a channel but activates calcium release from intracellular stores. It has long been known that calcium currents are dispensable for skeletal muscle contraction. However, the questions as to how and why the channel function of CaV1.1 is curtailed remained obscure until the recent discovery of a developmental CaV1.1 splice variant with normal channel functions. This discovery provided new means to study the molecular mechanisms regulating the channel gating and led to the understanding that in skeletal muscle, calcium currents need to be restricted to allow proper regulation of fibre type specification and to prevent mitochondrial damage.
Curtailing calcium influx during excitation–contraction coupling is critical for fibre type specification and mitochondrial integrity. In mammalian skeletal muscle, developmentally regulated splicing of CaV1.1 virtually abolishes calcium influx through the voltage-gated calcium channel. In fetal muscle the CaV1.1e splice variant lacking exon 29 activates L-type calcium currents (ICa) at physiologically depolarized membrane potentials and contributes significantly to the cytoplasmic calcium signals controlling contraction (Δ[Ca2+]). However, inclusion of exon 29 in the adult CaV1.1a shifts the voltage dependence of activation by +30 mV and eliminates the contribution of calcium influx to the cytoplasmic calcium signal. Alternative splicing of exon 29 controls channel gating without affecting activation of the ryanodine receptor (RyR1) using a unique molecular mechanism in the fourth voltage-sensing domain of the CaV1.1 channel. When inclusion of exon 29 fails in knock-out mice or in muscles of myotonic dystrophy patients, the increased calcium influx perturbs fibre type specification and causes mitochondrial damage.