Spontaneous β2-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, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

A receptor can be activated either by specific ligand-directed changes in conformation or by intrinsic, spontaneous conformational change. In the β2-adrenergic receptor (AR) overexpression transgenic (TG4) murine heart, spontaneously activated β2AR (β2-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 β2- R* differs from that of a ligand-elicited β2AR activation (β2-LR*). In ventricular myocytes from TG4 mice, the properties of L-type Ca2+ current (I(Ca)), a major effector of β2-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 wildtype (WT) cells. Although the contractile response to β2-R* in TG4 cells was abolished by a β2AR inverse agonist, ICI118,551 (5 X 10-7 M), or an inhibitory cAMP analog, Rp- CPT-cAMPS (10-4 M), no change was detected in the simultaneously recorded I(Ca). These results suggest that the increase in basal cAMP due to β2-R*, while increasing contraction amplitude, does not affect I(Ca) characteristics. In contrast, the β2AR agonist, zinterol elicited a substantial augmentation of I(Ca) 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 I(Ca) 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 β2-R* bypasses I(Ca), to modulate contraction, and that β2-LR* and β2-R* exhibit different intracellular signaling and target protein specificity.

Original languageEnglish (US)
Pages (from-to)485-493
Number of pages9
JournalMolecular Pharmacology
Volume56
Issue number3
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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