CaV1.2 and CaV1.3 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(V)1.2 and Ca(V)1.3 pore-forming subunits. To compare targeting of Ca(V)1.2 and Ca(V)1.3 L-type Ca2+ channels, we transfected rat hippocampal neuronal cultures with surface-epitope-tagged sHA-Ca(V)1.2 or sHA-Ca(V)1.3a constructs and found that: (i) both sHA-Ca(V)1.2 and sHA-Ca(V)1.3a form clusters on the neuronal plasma membrane surface; (ii) when compared with sHA-Ca(V)1.2 surface clusters, the sHA-Ca(V)1.3a surface clusters were 10% larger and 25% brighter, but 35% less abundant; (iii) 81% of sHA-Ca(V)1.2 surface clusters, but only 48% of sHA-Ca(V)1.3a surface clusters, co-localized with synapsin clusters; (iv) co-expression with GFP-Shank-1B had no significant effect on sHA-Ca(V)1.2 surface clusters, but promoted formation and synaptic localization of sHA-Ca(V)1.3a surface clusters. In experiments with dihydropyridine-resistant Ca(V)1.2 and Ca(V)1.3a mutants we demonstrated that Ca(V)1.3a 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(V)1.3 knockout mice we discovered that Ca(V)1.3 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(V)1.2 and Ca(V)1.3 L-type Ca2+ channels in the brain.