Molecular Mechanism of Calcium Channel Regulation in the Fight-or-Flight Response

作者：Fuller Matthew D; Emrick Michelle A; Sadilek Martin; Scheuer Todd; Catterall William A^*

来源：Science Signaling, 2010, 3(141): ra70.

DOI：10.1126/scisignal.2001152

During the fight-or-flight response, the sympathetic nervous system stimulates L-type calcium ion (Ca(2+)) currents conducted by Ca(V)1 channels through activation of beta-adrenergic receptors, adenylyl cyclase, and phosphorylation by adenosine 3',5'-monophosphate-dependent protein kinase [also known as protein kinase A (PKA)], increasing contractility of skeletal and cardiac muscles. We reconstituted this regulation of cardiac Ca(V)1.2 channels in non-muscle cells by forming an autoinhibitory signaling complex composed of Ca(V)1.2 Delta 1800 (a form of the channel truncated at the in vivo site of proteolytic processing), its noncovalently associated distal carboxyl-terminal domain, the auxiliary alpha(2)delta(1) and beta(2b) subunits, and A-kinase anchoring protein 15 (AKAP15). A factor of 3.6 range of Ca(V)1.2 channel activity was observed from a minimumin the presence of protein kinase inhibitors to a maximum upon activation of adenylyl cyclase. Basal Ca(V)1.2 channel activity in unstimulated cells was regulated by phosphorylation of serine-1700 and threonine-1704, two residues located at the interface between the distal and the proximal carboxyl-terminal regulatory domains, whereas further stimulation of channel activity through the PKA signaling pathway only required phosphorylation of serine-1700. Our results define a conceptual framework for Ca(V)1.2 channel regulation and identify sites of phosphorylation that regulate channel activity.

• 出版日期2010-9-28