title: Developmental activation of calmodulin-dependent facilitation of cerebellar P-type Ca2+ current.
abstract: P-type (CaV2.1) Ca2+ channels are a central conduit of neuronal Ca2+ entry, so their Ca2+ feedback regulation promises widespread neurobiological impact. Heterologous expression of recombinant CaV2.1 channels demonstrates that the Ca2+ sensor calmodulin can trigger Ca2+-dependent facilitation (CDF) of channel opening. This facilitation occurs when local Ca2+ influx through individual channels selectively activates the C-terminal lobe of calmodulin. In neurons, however, such calmodulin-mediated processes have yet to be detected, and CDF of native P-type current has thus far appeared different, arguably triggered by other Ca2+ sensing molecules. Here, in cerebellar Purkinje somata abundant with prototypic P-type channels, we find that the C-terminal lobe of calmodulin does produce CDF, and such facilitation augments Ca2+ entry during stimulation by repetitive action-potential and complex-spike waveforms. Beyond recapitulating key features of recombinant channels, these neurons exhibit an additional modulatory dimension: developmental upregulation of CDF during postnatal week 2. This phenomenon reflects increasing somatic expression of CaV2.1 splice variants that manifest CDF and progressive dendritic targeting of variants lacking CDF. Calmodulin-triggered facilitation is thus fundamental to native CaV2.1 and rapidly enhanced during early development.
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Dipayan
authors.initials: D
authors.lastname: Chaudhuri
authors.forename: Badr A
authors.initials: BA
authors.lastname: Alseikhan
authors.forename: Siao Yun
authors.initials: SY
authors.lastname: Chang
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000502:physiology*; D002147:Calmodulin / Q000494:pharmacology*; D002460:Cell Line; D002531:Cerebellum / Q000502:physiology; D006801:Humans; D007668:Kidney; D009553:Nimodipine / Q000494:pharmacology; D010957:Plasmids; D011689:Purkinje Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D002147:Calmodulin; D013779:Tetrodotoxin; D009553:Nimodipine