beta(2)-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart

Article

关键词: PHOSPHOLAMBAN PHOSPHORYLATION;    CALCIUM CHANNELS;    AUTORADIOGRAPHIC LOCALIZATION;    BETA-ADRENOCEPTORS;    ADENYLATE-CYCLASE;    CARDIAC MYOCYTES;    CA2+ CURRENT;    CYCLIC-AMP;    TROPONIN-I;    STIMULATION;   

DOI  :  10.1161/01.CIR.99.18.2458

来源: SCIE

【 摘 要 】

Background-Recent studies of beta-adrenergic receptor (beta-AR) subtype signaling in in vitro preparations have raised doubts as to whether the cAMP/protein kinase A (PKA) signaling is activated in the same manner in response to beta(2)-AR versus beta(1)-AR stimulation. Methods and Results-The present study compared, in the intact dog, the magnitude and characteristics of chronotropic, inotropic, and lusitropic effects of cAMP accumulation, PKA activation, and PKA-dependent phosphorylation of key effector proteins in response to beta-AR subtype stimulation. In addition, many of these parameters and L-type Ca2+ current (I-Ca) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA-dependent phosphorylation cascade activated by beta(1)-AR stimulation could explain the resultant modulation of cardiac function, substantial beta(1)-AR-mediated chronotropic, inotropic, and lusitropic responses occurred in the absence of PKA activation and phosphorylation of nonsarcolemmal proteins, including phospholamban, troponin I-Ca C protein, and glycogen phosphorylase kinase. However, in single canine myocytes, we found that beta(2)-AR-stimulated increases in both I-Ca and contraction were abolished by PKA inhibition. Thus, the beta(2)-AR-directed cAMP/PKA signaling modulates sarcolemmal L-type Ca2+ channels but does not regulate PKA-dependent phosphorylation of cytoplasmic proteins. Conclusions-These results indicate that the dissociation of beta(2)-AR signaling from cAMP regulatory systems is only apparent and that beta(2)-AR-stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling.

【 授权许可】

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