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ATP-sensitive K⁺ channel activation by calcitonin gene-related peptide and protein kinase A in pig coronary arterial smooth muscle

G. C. Wellman, J. M. Quayle and N. B. Standen

1. We used patch clamp to study whole-cell K⁺ currents activated by calcitonin gene-related peptide (CGRP) in smooth muscle cells freshly dissociated from pig coronary arteries.

2. CGRP (50 nM) activated an inward current at -60 mV in symmetrical 140 mM K⁺ that was blocked by glibenclamide (10 µM), an inhibitor of ATP-sensitive potassium (K_ATP) channels. CGRP-induced currents were larger in cells dialysed with 0·1 mM ATP than with 3·0 mM ATP.

3. Forskolin (10 µM) activated a glibenclamide-sensitive current, as did intracellular dialysis with cAMP (100 µM). The catalytic subunit of cAMP-dependent protein kinase (protein kinase A, PKA), added to the pipette solution, activated equivalent currents in five out of twelve cells.

4. CGRP-induced currents were reduced by the PKA inhibitors adenosine 3',5'-cyclic monophosphorothioate, R_P-isomer, triethylammonium salt (Rp-cAMPS; 100 µM) and N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulphonamide dihydrochloride (H-89; 1 µM), and abolished by inclusion of a PKA inhibitor peptide in the pipette solution.

5. The -adrenergic agonist isoprenaline (10 µM) also activated a glibenclamide-sensitive K⁺ current.

6. CGRP-induced currents were unaffected by the inhibitor of cGMP-dependent protein kinase (PKG) KT5823 (1 µM). Sodium nitroprusside (10 µM) did not activate a glibenclamide-sensitive current in cells held at -60 mV, but did activate an outward current at +60 mV that was abolished by KT5823, or by 100 nM iberiotoxin (an inhibitor of BK_Ca channels).

7. Our findings suggest that CGRP activates coronary K_ATP channels through a pathway that involves adenylyl cyclase and PKA, but not PKG.

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