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Protein kinase A‐mediated inhibition of T‐type Ca 2+ channels in the cerebral circulation
Author(s) -
Harraz Osama F,
Welsh Donald G
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.870.12
Subject(s) - forskolin , nifedipine , chemistry , electrophysiology , biophysics , protein kinase a , patch clamp , voltage dependent calcium channel , voltage clamp , endocrinology , medicine , membrane potential , kinase , calcium , biochemistry , biology , in vitro , organic chemistry
Previous work from our laboratory documented the expression of L‐type (Ca V 1.2) and T‐type (Ca V 3.1/Ca V 3.2) Ca 2+ channels in rat cerebral arterial smooth muscle. In this study, we examine, in greater detail, the electrophysiological and regulatory properties of these voltage‐gated Ca 2+ channels. Using whole‐cell patch clamp electrophysiology and Ba 2+ as charge carrier, whole‐cell Ba 2+ current was pharmacologically subdivided into nifedipine‐sensitive and ‐insensitive components. The nifedipine‐sensitive component displayed L‐type characteristics such as slow activation/inactivation at depolarized voltages. In contrast, the nifedipine‐insensitive current displayed T‐type Ca 2+ channel properties such as fast activation/inactivation; this current could be further subdivided into Ca V 3.1 and Ca V 3.2 components based on Ni 2+ sensitivity. Modulators of Protein kinase A (PKA) were found to affect T‐type, but not the L‐type Ca 2+ channel activity in cerebral arterial smooth muscle. In greater detail, PKA activators (isoproterenol, forskolin and db‐cAMP) were observed to inhibit peak T‐type Ca 2+ current and evoke a leftward shift in the activation/inactivation kinetics. While PKA inhibitors (KT5720, PKI 14–22) did not alter the magnitude of the T‐type Ca 2+ channel current, they did prevent forskolin‐mediated inhibition. Forskolin's inhibitory effect on the T‐type Ca 2+ channel was similarly abolished by stHt31, a peptide inhibitor of A‐kinase anchoring protein. In summary, the study provides the first detailed electrophysiological delineation of L‐ and T‐type Ca 2+ channels in cerebral arterial smooth muscle. Intriguingly, it shows that T‐type Ca 2+ channels are also selectively targeted by signaling pathways that mediate arterial vasodilation.