A Mechanism for the Direct Regulation of T-Type Calcium Channels by Ca 2+/Calmodulin-Dependent Kinase II

Abstract

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 α1H, channels (Cav3.2), by Ca2+/CaM-dependent protein kinase II (CaMKII). We show that channel regulation is selective for the LVA α1H, Ca2+ channel subtype, depends on determinants in the α1HII-III intracellular loop, and requires the phosphorylation of a serine residue absent from unregulated α 1G (Cav3.1) channels. These studies identify the α1H 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.