A mechanism for the direct regulation of T-type calcium channels by Ca2+/calmodulin-dependent kinase II

Low-voltage-activated (LVA) Ca2+ channels are widely distributed throughout the CNS and are important determinants of neuronal excitability, initiating dendritic and somatic Ca2+ spikes that trigger and shape the pattern of action potential firing. Here, we define a molecular mechanism underlying the dynamic regulation of alpha(1H) channels (Ca(v)3.2), by Ca2+/CaM-dependent protein kinase II ( CaMKII). We show that channel regulation is selective for the LVA alpha(1H) Ca2+ channel subtype, depends on determinants in the alpha(1H) II-III intracellular loop, and requires the phosphorylation of a serine residue absent from unregulated alpha(1G) (Ca(v)3.1) channels. These studies identify the alpha(1H) channel as a new substrate for CaMKII and provide the first molecular mechanism for the direct regulation of T-type Ca2+ channels by a protein kinase. Our data suggest a novel mechanism for modulating the integrative properties of neurons.