Meta-Biol

• Pathways

Voltage-dependent L-type calcium channels (LTCCs) transport Ca2+ into excitable cells. Isoforms CACNA1C, D, F and S form long-lasting (L-type) inward Ca2+ currents (I_CaL) and play an important role in excitation-contraction coupling in the heart. LTCCs are multisubunit complexes consisting of alpha-1, alpha-2/delta, beta and gamma subunits in a 1:1:1:1 ratio (Brust et al. 1993). The alpha-2 and delta subunits in these complexes are chains of differing length cleaved from the same gene product (CACNA2D), linked by a disulfide bond (Calderon-Rivera et al. 2012). Pore-forming alpha1 subunits are supported by the auxiliary alpha-2, delta and beta subunits which aid the membrane trafficking of the alpha1 subunit and modulate the kinetic properties of the channel (Klugbauer et al. 2003, Yang et al. 2011). The binding of various gamma subunits to alpha1 subunits may differentially modulate alpha1 subunit function in the heart (Yang et al. 2011). In heart pacemaker cells, phase 0 of the action potential depends upon LTCC-mediated Ca2+ current rather than the fast Na+ current. In cardiac pacemaker cells, phase 1 is due to the closure of LTCCs (and rapid efflux of K+). Specific subunits can form the LTCC in the heart are CACNA1C (pore-forming alpha subunit), CACNA2D2 (alpha-2:delta-2 subunit), CACNB1 and CANCNB2 (either of these beta subunits) and CACNG4, 6, 7 and 8 (any of these gamma subunits).