Abstract

Structural diversity of voltage-gated Ca channels underlies much of the functional diversity in Ca signaling in neurons. Alternative splicing is an important mechanism for generating structural variants within a single gene family. In this paper, we show the expression pattern of an alternatively spliced 21 amino acid encoding exon in the II–III cytoplasmic loop region of the N-type Ca channel α_1B subunit and assess its functional impact. Exon-containing α_1B mRNA dominated in sympathetic ganglia and was present in ∼50% of α_1B mRNA in spinal cord and caudal regions of the brain and in the minority of α_1B mRNA in neocortex, hippocampus, and cerebellum (<20%). The II–III loop exon affected voltage-dependent inactivation of the N-type Ca channel. Steady-state inactivation curves were shifted to more depolarized potentials without affects on either the rate or voltage dependence of channel opening. Differences in voltage-dependent inactivation between α_1Bsplice variants were most clearly manifested in the presence of Ca channel β_1b or β₄, rather than β_2a or β₃, subunits. Our results suggest that exon-lacking α_1B splice variants that associate with β_1b and β₄ subunits will be susceptible to voltage-dependent inactivation at voltages in the range of neuronal resting membrane potentials (−60 to −80 mV). In contrast, α_1B splice variants that associate with either β_2a or β₃ subunits will be relatively resistant to inactivation at these voltages. The potential to mix and match multiple α_1B splice variants and β subunits probably represents a mechanism for controlling the plasticity of excitation–secretion coupling at different synapses.