Journal article
Spontaneous β 2 -Adrenergic Signaling Fails To Modulate L-Type Ca 2+ Current in Mouse Ventricular Myocytes
Molecular pharmacology, Vol.56(3), pp.485-493
09/01/1999
DOI: 10.1124/mol.56.3.485
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.
Details
- Title: Subtitle
- Spontaneous β 2 -Adrenergic Signaling Fails To Modulate L-Type Ca 2+ Current in Mouse Ventricular Myocytes
- Creators
- Ying-Ying Zhou - National Institute on AgingHeping Cheng - National Institute on AgingLong-Sheng Song - National Institute on AgingDingji Wang - National Institute on AgingEdward G. Lakatta - National Institute on AgingRui-Ping Xiao - National Institute on Aging
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.56(3), pp.485-493
- DOI
- 10.1124/mol.56.3.485
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Language
- English
- Date published
- 09/01/1999
- Academic Unit
- Biochemistry and Molecular Biology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984288723502771
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