Neuronal CaV1.3α1L-Type Channels Activate at Relatively Hyperpolarized Membrane Potentials and Are Incompletely Inhibited by Dihydropyridines

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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 (CaV1.2α1 and CaV1.3α1). 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 CaV1.3α1 L-type channels activate at membrane potentials ∼25 mV more hyperpolarized, compared with CaV1.2α1. This unusually negative activation threshold for CaV1.3α1 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 obscured the unique voltage-dependent properties of CaV1.3α1 in certain previous studies. We also demonstrate that CaV1.3α1 channels are pharmacologically distinct from CaV1.2α1. The IC50for nimodipine block of CaV1.3α1 L-type calcium channel currents is 2.7 ± 0.3 μm, a value 20-fold higher than the concentration required to block CaV1.2α1. The relatively low sensitivity of the CaV1.3α1 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 Cav1.3α1.