In vivo desensitization of glycogenolysis to Ca2+-mobilizing hormones in rat liver cells.
Rat hepatocytes contain several types of Ca2+-linked receptors, all of which stimulate glycogen breakdown by increasing cytosolic free Ca2+ concentration [( Ca2+]c). In vivo desensitization of this Ca2+ messenger system was studied in hepatocytes isolated from either pheochromocytoma (PHEO)-harboring and chronically norepinephrine (NE)-infused rats. Homologous desensitization for alpha 1-adrenergic receptor-mediated phosphorylase activation developed in the early stage of PHEO rats (3-4 wk after implantation), whereas, in the later stage of tumor development or in the NE-infused rats, phosphorylase responses to all Ca2+-mobilizing stimulations were subsensitive (heterologous desensitization). In the homologous desensitization, the [Ca2+]c response to alpha 1-adrenergic stimulation was selectively reduced. We found, using the phenoxybenzamine inactivation method, that there was a linear relationship between alpha 1 receptor density and the [Ca2+]c response; consequently, the blunted [Ca2+]c response to alpha 1-adrenergic stimulation could not be explained by the 34% downregulation of alpha 1 receptors seen in these rats. These results indicated that uncoupling at a step proximal to alpha 1 receptor-stimulated [Ca2+]c increase is also of primary importance in homologous desensitization of phosphorylase activation. On the other hand, heterologous desensitization also involved alteration(s) at steps distal to the rise in [Ca2+]c. Our data demonstrate that prolonged exposure to catecholamines results in desensitization of the [Ca2+]c mobilization pathway and may involve multiple mechanisms.
Tsujimoto
G
G
Department of Pharmacology, Yamanashi Medical College, Japan.
Tsujimoto
A
A
Kato
K
K
Hashimoto
K
K
D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010673:Pheochromocytoma / Q000378:metabolism; D006005:Phosphorylases / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D015290:Second Messenger Systems
D006728:Hormones; D008112:Liver Glycogen; D011942:Receptors, Adrenergic, alpha; D010643:Phenoxybenzamine; D000804:Angiotensin II; D001127:Arginine Vasopressin; D005576:Colforsin; D010656:Phenylephrine; D000001:Calcimycin; D003994:Bucladesine; D005934:Glucagon; D006005:Phosphorylases; D002118:Calcium; D009638:Norepinephrine; D011224:Prazosin