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Vol. 56, Issue 3, 485-493, September 1999
2-Adrenergic Signaling Fails To
Modulate L-Type Ca2+ Current in Mouse Ventricular
Myocytes
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 
2-adrenergic receptor (AR) overexpression transgenic (TG4) murine heart, spontaneously activated 2AR
(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
2-R* differs from that of a ligand-elicited
2AR activation (2-LR*). In ventricular myocytes from TG4 mice, the properties of L-type
Ca2+ current (ICa), a major effector of
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 2-R* in TG4
cells was abolished by a 2AR inverse agonist, ICI118,551
(5 × 10
7 M), or an inhibitory cAMP analog,
Rp-CPT-cAMPS (104 M), no change was detected in the
simultaneously recorded ICa. These results suggest that the
increase in basal cAMP due to 2-R*, while increasing
contraction amplitude, does not affect ICa characteristics. In contrast, the 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 2-R* bypasses ICa to
modulate contraction, and that 2-LR* and
2-R* exhibit different intracellular signaling and
target protein specificity.
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