Research & Drug Development

Voltage-gated calcium channels (VGCC) mediate transient increases in cytoplasmic calcium concentration in response to membrane depolarisation triggering different physiological events such as neuronal excitability, muscle contraction, secretion, neurotransmission, gene expression and gating of other channels. VGCC are formed by as many as four distinct subunits (a1, a2d, b, g). The a1 subunit can form a functional calcium channel and is comprised of four repeated domains, each containing six trans-membrane regions. The a2d subunit affects the biophysical properties of the channel and is associated with increased channel expression. The b subunit binds to the a1 subunit causing different shifts in the kinetics and voltage dependence of gating and the g subunit is involved in modulating the biophysical properties of the channel.

So far ten a1 -subunit genes are known, that define ten different calcium channel subtypes. These are classified in three families (Cav1, Cav2, Cav3) according to the main biophysical and pharmacological properties of the currents they underlie, L-type, N, P/Q, R-type, and T-type currents, respectively. Calcium channels belonging to the Cav1 family (Cav1.1 to Cav1.4) require strong depolarisation for activation and mediate L-type calcium currents that constitute the main calcium currents recorded in muscle and endocrine cells. P/Q-type, N-type and R-type calcium currents are carried by channel subtypes grouped in the Cav2 family (Cav2.1, Cav2.2 and Cav2.3 respectively). They require strong depolarisation for activation and are expressed primarily in neurones, where they initiate neurotransmission at most fast synapses and also mediate calcium entry into cell bodies and dendrites. T-type calcium currents are activated by weak depolarisation and are transient. They are expressed in a wide variety of cell types, where they are involved in shaping the action potential and controlling patterns of repetitive firing.