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(Circulation Research. 1995;76:832-838.)
© 1995 American Heart Association, Inc.

Articles

Cardiac Muscarinic Potassium Channel Activity Is Attenuated by Inhibitors of G_ß

Lawrence A. Nair, James Inglese, Robert Stoffel, Walter J. Koch, Robert J. Lefkowitz, Madan M. Kwatra, Augustus O. Grant

From the Departments of Medicine, Biochemistry, and Anesthesiology and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC.

Correspondence to Augustus O. Grant, MD, Box 3504, Duke University Medical Center, Durham, NC 27710.

Abstract The cardiac muscarinic potassium channel (I_K.ACh) is activated by a G protein upon receptor stimulation with acetylcholine. The G protein subunit responsible for activation (G versus G_ß) has been disputed. We used G_ß inhibitors derived from the ß-adrenergic kinase 1 (ßARK1) to assess the relative importance of G_ß in I_K.ACh activation. In rabbit atrial myocytes, I_K.ACh had a conductance of 49±6.2 pS. In inside-out patches, the mean open time was 1.60±0.57 ms, mean time constant (_o) was 1.59±0.53 ms, and mean closed time was 3.02±1.35 ms (n=38). ßARK1 is a G_ß-sensitive enzyme that interacts with G_ß through a defined sequence near its carboxyl terminus. A 28-amino-acid peptide derived from the carboxyl terminus of ßARK1 (peptide G) increased the closed time to 10.04 ms (P<.001) and decreased opening probability (NP_o) by 71% (P<.001). Fusion proteins containing the entire carboxyl terminus of ßARK1, glutathione S-transferase ßARK1ct and hexahistidine ßARK1ct, decreased NP_o by 67% (P=.03) and 48% (P=.009), respectively. They also both significantly increased the closed time. None of the inhibitors affected mean open time or channel amplitude. A control peptide derived from a neighboring region of ßARK1 had no significant effect on I_K.ACh activity. These results provide further evidence for the role of G_ß in the activation of I_K.ACh.

Key Words: muscarinic receptor • potassium channel • G protein • ß-adrenergic receptor kinase

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