Myocyte response to stimulation of receptors and ion channels.
Ventricular myocytes dissociated from adult rat heart and cultured chick embryo ventricular cells were utilized to examine mechanisms by which neurotransmitters, hormones, and ontogeny modulate expression and function of beta-adrenergic receptors and L-type calcium channels. Either freshly dissociated cells or cultured cells were studied by an optical-video system to characterize contractility and, in some instances, by a microspectrofluorimeter to determine [Ca2+]i as reported by fura 2. Ligand binding studies in intact cells and membranes were conducted with receptor and ion channel antagonists and agonists. Exposure of intact cells to isoproterenol produced contractile de-sensitization, loss of high affinity receptors from the sarcolemma and closely coupled decline in hormone-sensitive adenylate cyclase activity. De-sensitization was by a microfilament-dependent process. Down-regulation depended upon microtubular function. During development of the chick heart, there was an increase in number of dihydropyridine binding sites, taken as a measure of number of L-type calcium channels, at a time when sensitivity to [Ca2+]o and to Bay k 8644 declined. Thyroid hormone was capable of up-regulating L-type calcium channels. Prolonged exposure to a beta-adrenergic agonist produced coordinate down-regulation of beta-receptors and calcium channels. Down-regulation was a cAMP-dependent process. Thus, the beta-adrenergic receptor and a distal component of the effector-response coupling system, the L-type calcium channel, can be regulated independently and in concert by physiologically and pathophysiologically important mechanisms.
Marsh
J D
JD
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002395:Catecholamines / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D006321:Heart / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013268:Stimulation, Chemical; D013963:Thyroid Hormones / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D013963:Thyroid Hormones