Neuronal Ca_V1.3α₁L-Type Channels Activate at Relatively Hyperpolarized Membrane Potentials and Are Incompletely Inhibited by Dihydropyridines

Abstract

L-type calcium channels regulate a diverse array of cellular functions within excitable cells. Of the four molecularly defined subclasses of L-type Ca channels, two are expressed ubiquitously in the mammalian nervous system (Ca V 1.2 1 and Ca V 1.3 1 ). Despite diversity at the molecular level, neuronal L-type channels are generally assumed to be functionally and pharmacologically similar, i.e., high-voltage activated and highly sensitive to dihydropyridines. We now show that Ca V 1.3 1 L-type channels activate at membrane potentials 25 mV more hyperpolarized, compared with Ca V 1.2 1 . This unusually negative activation threshold for Ca V 1.3 1 channels is independent of the specific auxiliary subunits coexpressed, of alternative splicing in domains I-II, IVS3-IVS4, and the C terminus, and of the expression system. The use of high concentrations of extracellular divalent cations has possibly ob-scured the unique voltage-dependent properties of Ca V 1.3 1 in certain previous studies. We also demonstrate that Ca V 1.3 1 channels are pharmacologically distinct from Ca V 1.2 1 . The IC 50 for nimodipine block of Ca V 1.3 1 L-type calcium channel currents is 2.7 0.3 M, a value 20-fold higher than the concentration required to block Ca V 1.2 1 . The relatively low sensitivity of the Ca V 1.3 1 subunit to inhibition by dihydropyridine is unaffected by alternative splicing in the IVS3-IVS4 linker. Our results suggest that functional and pharmacological criteria used commonly to distinguish among different Ca currents greatly underestimate the biological importance of L-type channels in cells expressing Ca v 1.3 1 .