Bone remodeling signaled by a dihydropyridine- and phenylalkylamine-sensitive calcium channel.
An osteoblast calcium channel demonstrated by single channel recordings is associated with calcium antagonist receptor binding sites in osteoblast-like osteosarcoma cells. By using whole cell current recordings we now show that this channel is stimulated by the dihydropyridine calcium agonist drug BAY K 8644. A physiological relevance of these channels is apparent from the stereoselective, potent inhibition of parathyroid hormone-stimulated calcium uptake into osteoblast-like cells in culture by desmethoxyverapamil, a phenylalkylamine calcium antagonist. Secretion by these cells of the bone matrix protein osteocalcin is stimulated by BAY K 8644 and blocked by desmethoxyverapamil and nitrendipine. Evidence for a role of this channel in bone remodeling in intact animals comes from enhanced bone resorption in fetal rat bones observed with BAY K 8644 and stereoselective, potent blockade of resorption by desmethoxyverapamil.
Guggino
S E
SE
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Lajeunesse
D
D
Wagner
J A
JA
Snyder
S H
SH
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001846:Bone Development; D001862:Bone Resorption / Q000187:drug effects*; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D004553:Electric Conductivity; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology; D013237:Stereoisomerism
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D004095:Dihydropyridines; D010281:Parathyroid Hormone; D011978:Receptors, Nicotinic; D015675:Osteocalcin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium