Molecular elements of ion permeation and selectivity within calcium channels

Voltage-dependent calcium channels are located in the plasma membrane and f orm a highly selective conduit by which Ca2+ ions enter all excitable cells and some nonexcitable cells. Extensive characterization studies have revea led the existence of one low (T) and five high-voltage-activated calcium ch annel types (L, N, P, Q, and R). The high voltage-activated calcium channel s have been found to exist as heteromultimers, consisting of an alpha(1), b eta, alpha(2)/delta, and gamma subunit. Molecular cloning has revealed the existence of 10 channel transcripts, and expression of these cloned calcium channel genes has shown that basic voltage-activated calcium channel funct ion is strictly carried by the corresponding a, subunits. In turn, the auxi liary subunits serve to modulate calcium channel function by altering the v oltage dependence of channel gating, kinetics, and current amplitude, there by creating a likelihood for calcium channels with multiple properties. Alt hough for calcium channels to be effective, Ca2+ ions must enter selectivel y through the pore of the alpha(1)-subunit, bypassing competition with othe r extracellular ions. The structural determinants of this highly selective Ca2+ filter reside within the four glutamic acid residues located at homolo gous positions within each of the four pore-forming segments. Together, the se residues form a single or multiple Ca2+ affinity site(s) that entrap cal cium ions, which are then electrostatically repulsed through the intracellu lar opening of the pore. This mechanism of high-selectivity calcium filtrat ion, the spatial arrangement of pore glutamic acid residues; and the coordi nation chemistry of calcium binding are discussed in this review.