Mapping of dihydropyridine binding residues in a less sensitive invertebrate L-type calcium channel (LCav1)

Abstract

Invertebrate L-type calcium channel, LCav1, isolated from the pond snail Lymnaea stagnalis is nearly indistinguishable from mammalian Ca v1.2 (α1C) calcium channel in biophysical characteristics observed in vitro. These L-type channels are likely constrained within a narrow range of biophysical parameters to perform similar functions in the snail and mammalian cardiovascular systems. What distinguishes snail and mammalian L-type channels is a difference in dihydropyridine sensitivity: 100 nM isradipine exhibits a significant block of mammalian Cav1.2 currents without effect on snail LCav1 currents. The native snail channel serves as a valuable surrogate for validating key residue differences identified from previous experimental and molecular modeling work. As predicted, three residue changes in LCav1 (N-3o18, F-3i10 and I-4i12) replaced with Dhp-sensing residues in respective positions of Cav1.2, (Q-3o18, Y-3i10 and M-4i12) raises the potency of isradipine block of LCav1 channels to that of mammalian Cav1.2. Interestingly, the single N-3o18-Q mutation in LCav1 channels lowers Dhp sensitivity even further and the triple mutation bearing enhanced isradipine sensitivity still retains a reduced potency of agonist, (s)-Bay K8644. © 2011 Landes Bioscience.