Ca_V1.2 and Ca_V1.3 neuronal L-type calcium channels: Differential targeting and signaling to pCREB

Neurons express multiple types of voltage-gated calcium (Ca²⁺) channels. Two subtypes of neuronal L-type Ca²⁺ channels are encoded by Ca_V1.2 and Ca_V1.3 pore-forming subunits. To compare targeting of Ca_V1.2 and Ca_V1.3 L-type Ca²⁺ channels, we transfected rat hippocampal neuronal cultures with surface-epitope-tagged sHA-Ca_V1.2 or sHA-Ca_V1.3a constructs and found that: (i) both sHA-Ca_V1.2 and sHA-Ca _V1.3a form clusters on the neuronal plasma membrane surface; (ii) when compared with sHA-Ca_V1.2 surface clusters, the sHA-Ca _V1.3a surface clusters were 10% larger and 25% brighter, but 35% less abundant; (iii) 81% of sHA-Ca_V1.2 surface clusters, but only 48% of sHA-Ca_V1.3a surface clusters, co-localized with synapsin clusters; (iv) co-expression with GFP-Shank-1B had no significant effect on sHA-Ca _V1.2 surface clusters, but promoted formation and synaptic localization of sHA-Ca_V1.3a surface clusters. In experiments with dihydropyridine-resistant Ca_V1.2 and Ca_V1.3a mutants we demonstrated that Ca_V1.3a L-type Ca²⁺ channels preferentially mediate nuclear pCREB signaling in hippocampal neurons at low, but not at high, levels of stimulation. In experiments with primary neuronal cultures from Ca_V1.3 knockout mice we discovered that Ca _V1.3 channels play a more important role in pCREB signaling in striatal medium spiny neurons than in hippocampal neurons. Our results provide novel insights into the function of Ca_V1.2 and Ca_V1.3 L-type Ca²⁺ channels in the brain.