title: Regulation of inositol 1,4,5-trisphosphate metabolism by guanine nucleotides in membranes of cultured newborn rat cardiomyocytes.
abstract: Membranes of cultured newborn rat cardiomyocytes contain enzymatic activities that regulate the formation and the breakdown of inositol 1,4,5-trisphosphate (1,4,5-IP3). GTP gamma S increased the rate of exogenous [3H]phosphatidyl 4,5-bisphosphate ([3H]PIP2) hydrolysis (EC50: 40 microM). This effect was dependent on the presence of deoxycholate and maximal at 2 mM deoxycholate. GTP gamma S increased the efficacy of phospholipase C (PLC) (by 2.3-fold), but did not alter the apparent affinity of the enzyme for PIP2. Other nucleotides, GDP beta S and ATP gamma S, and pyrophosphate also stimulated PIP2 hydrolysis, while AlF4- was ineffective. The effect of GTP gamma S was not inhibited by GDP beta S. The agonists norepinephrine and thrombin, which by themselves had no effect, did not potentiate the response to GTP gamma S. In contrast, 1,4,5-IP3 hydrolysis was decreased by GTP gamma S (EC50: 100 microM) as well as by other nucleotides and by pyrophosphate, but not by AlF4-. GDP beta S did not antagonize the GTP gamma S-induced inhibition of IP3 hydrolysis. These results suggest that GTP can stimulate the hydrolysis of exogenous PIP2 by an action on membrane-bound PLC at a site beyond the G protein activating PLC and inhibit the hydrolysis of 1,4,5-IP3 by a mechanism common to all nucleotides. Thus, GTP can regulate 1,4,5-IP3 metabolism by stimulating its formation and inhibiting its breakdown.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Y
authors.initials: Y
authors.lastname: Vulliemoz
authors.forename: F
authors.initials: F
authors.lastname: Huber
authors.forename: J P
authors.initials: JP
authors.lastname: Bilezikian
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000535:Aluminum / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D011756:Diphosphates / Q000494:pharmacology; D005461:Fluorine / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives; D006321:Heart / Q000187:drug effects*; D006868:Hydrolysis / Q000187:drug effects; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D007295:Inositol Phosphates / Q000032:analysis; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D011756:Diphosphates; D006150:Guanine Nucleotides; D007295:Inositol Phosphates; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; C053629:fluoroaluminum; D005461:Fluorine; D015544:Inositol 1,4,5-Trisphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D000535:Aluminum; D010738:Type C Phospholipases; C003319:sodium pyrophosphate