Alternative splicing in the cytoplasmic II-III loop of the N-type Ca channel alpha(1B) subunit: Functional differences are beta subunit-specific

Structural diversity of voltage-gated Ca channels underlies much of the fun ctional diversity in Ca signaling in neurons. Alternative splicing is an im portant mechanism for generating structural variants within a single gene f amily. In this paper, we show the expression pattern of an alternatively sp liced 21 amino acid encoding exon in the II-III cytoplasmic loop region of the N-type Ca channel alpha(1B) subunit and assess its functional impact. E xon-containing alpha(1B) mRNA dominated in sympathetic ganglia and was pres ent in similar to 50% of alpha(1B) mRNA in spinal cord and caudal regions o f the brain and in the minority of alpha(1B) mRNA in neocortex, hippocampus , and cerebellum (<20%). The II-III loop exon affected voltage-dependent in activation of the N-type Ca channel. Steady-state inactivation curves were shifted to more depolarized potentials without affects on either the rate o r voltage dependence of channel opening. Differences in voltage-dependent i nactivation between alpha(1B) splice variants were most clearly manifested in the presence of Ca channel beta(1b) or beta(4), rather than beta(2a) or beta(3), subunits. Our results suggest that exon-lacking alpha(1B) splice v ariants that associate with beta(1b) and beta(4) subunits will be susceptib le to voltage-dependent inactivation at voltages in the range of neuronal r esting membrane potentials (-60 to -80 mV). In contrast, alpha(1B) splice v ariants that associate with either beta(2a) or beta(3) subunits will be rel atively resistant to inactivation at these voltages. The potential to mix a nd match multiple alpha(1B) splice variants and beta subunits probably repr esents a mechanism for controlling the plasticity of excitation-secretion c oupling at different synapses.