Mechanism of dopamine-mediated activation of BK channels in human coronary artery smooth muscle cells
Natarajan, Aruna Ramachandran.
Thesis (Ph.D.)--Georgetown University, 2008.; Includes bibliographical references. Coronary artery disease (CAD) is an important cause of morbidity and mortality worldwide and is associated with a sustained increase in vascular tone. Large conductance, voltage-dependent and calcium-activated potassium (K) channels, or BK channels determine membrane electrical activity in human coronary artery smooth muscle cells (HCASMCs). Their activation leads to hyperpolarization, a decrease in coronary vascular tone and vasorelaxation. Dopamine, via the D1-like receptors, activates K channels, and may play a role in CAD. Dopamine has been shown to activate BK channels or ATP-sensitive K channels in previous studies in porcine coronary myocytes. The effects of dopamine receptor activation on K channels in human coronary artery smooth muscle cells (HCASMCs) are not known. Further, there are two D1-like receptors, D1R and D5R. We hypothesize that the specific D1-like receptor involved in K channel activation is the D5R, that the specific K channel it activates is the BK channel and that the downstream cell signaling mechanisms mediating this effect in HCASMCs involve the cyclic GMP-related protein kinase (PKG). K channel responses to D1-like receptor agonists and antagonists were characterized and studied by cell-attached patch-clamp in HCASMCs in the presence and absence of the PKG antagonist KT 5823. In the absence of known ligands selective for D1R or D5R, the D1-like receptor involved was identified by using sequence-specific antisense (AS) oligonucleotides against human D1R or D5R; scrambled (Scr) oligonucleotides and non-transfected cells served as controls. D1-like receptor agonists activated BK channels in all groups except in those transfected with D5R As oligonucleotides, and non-transfected cells pretreated with KT 5823. These data suggest that dopamine activation of BK channels in HCASMCs is mediated by the D5R, via PKG. This is the first study to demonstrate differential D1-like receptor regulation of vascular smooth muscle function and identifies a novel receptor and signaling mechanism, which could be targeted to ameliorate the course of CAD.
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