Yy. Zhou et al., Spontaneous beta(2)-adrenergic signaling fails to modulate L-type Ca2+ current in mouse ventricular myocytes, MOLEC PHARM, 56(3), 1999, pp. 485-493
A receptor can be activated either by specific ligand-directed changes in c
onformation or by intrinsic, spontaneous conformational change. In the beta
(2)-adrenergic receptor (AR) overexpression transgenic (TG4) murine heart,
spontaneously activated beta(2)AR (beta(2)-R*) in the absence of ligands ha
s been evidenced by elevated basal adenylyl cyclase activity and cardiac fu
nction. In the present study, we determined whether the signaling mediated
by beta(2)-R* differs from that of a ligand-elicited beta(2)AR activation (
beta(2)-LR*). In ventricular myocytes from TG4 mice, the properties of L-ty
pe Ca2+ current (I-Ca), a major effector of beta(2)-LR* signaling, was unal
tered, despite a 2.5-fold increase in the basal cAMP level and a 1.9-fold i
ncrease in baseline contraction amplitude as compared with that of wildtype
(WT) cells. Although the contractile response to beta(2)-R* in TG4 cells w
as abolished by a beta(2)AR 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 increas
e in basal cAMP due to beta(2)-R*, while increasing contraction amplitude,
does not affect I,, characteristics. In contrast, the beta(2)AR agonist, zi
nterol elicited a substantial augmentation of I-Ca in both TG4 and WT cells
(pertussis toxin-treated), indicating that L-type Ca2+ channel in these ce
lls can respond to ligand-directed signaling. Furthermore, forskolin, an ad
enylyl cyclase activator, elicited similar dose-dependent increase in I-Ca
amplitude in WT and TG4 cells, suggesting that the sensitivity of L-type Ca
2+ channel to cAMP-dependent modulation remains intact in TG4 cells. Thus,
we conclude that beta(2)R* bypasses I-Ca to modulate contraction, and that
beta(2)-LR* and beta(2)-R* exhibit different intracellular signaling and ta
rget protein specificity.