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Vol. 56, Issue 3, 485-493, September 1999

Spontaneous beta 2-Adrenergic Signaling Fails To Modulate L-Type Ca2+ Current in Mouse Ventricular Myocytes

Ying-Ying Zhou, Heping Cheng, Long-Sheng Song, Dingji Wang, Edward G. Lakatta, and Rui-Ping Xiao

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland

A receptor can be activated either by specific ligand-directed changes in conformation or by intrinsic, spontaneous conformational change. In the beta 2-adrenergic receptor (AR) overexpression transgenic (TG4) murine heart, spontaneously activated beta 2AR (beta 2-R*) in the absence of ligands has been evidenced by elevated basal adenylyl cyclase activity and cardiac function. In the present study, we determined whether the signaling mediated by beta 2-R* differs from that of a ligand-elicited beta 2AR activation (beta 2-LR*). In ventricular myocytes from TG4 mice, the properties of L-type Ca2+ current (ICa), a major effector of beta 2-LR* signaling, was unaltered, despite a 2.5-fold increase in the basal cAMP level and a 1.9-fold increase in baseline contraction amplitude as compared with that of wild-type (WT) cells. Although the contractile response to beta 2-R* in TG4 cells was abolished by a beta 2AR inverse agonist, ICI118,551 (5 × 10-7 M), or an inhibitory cAMP analog, Rp-CPT-cAMPS (10-4 M), no change was detected in the simultaneously recorded ICa. These results suggest that the increase in basal cAMP due to beta 2-R*, while increasing contraction amplitude, does not affect ICa characteristics. In contrast, the beta 2AR agonist, zinterol elicited a substantial augmentation of ICa in both TG4 and WT cells (pertussis toxin-treated), indicating that L-type Ca2+ channel in these cells can respond to ligand-directed signaling. Furthermore, forskolin, an adenylyl cyclase activator, elicited similar dose-dependent increase in ICa amplitude in WT and TG4 cells, suggesting that the sensitivity of L-type Ca2+ channel to cAMP-dependent modulation remains intact in TG4 cells. Thus, we conclude that beta 2-R* bypasses ICa to modulate contraction, and that beta 2-LR* and beta 2-R* exhibit different intracellular signaling and target protein specificity.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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