title: Ins(1,4,5)P(3) regulates phospholipase Cbeta1 expression in cardiomyocytes.
abstract: The functional significance of the Ca2+-releasing second messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P(3), IP(3)) in the heart has been controversial. Ins(1,4,5)P(3) is generated from the precursor lipid phosphatidylinositol(4,5)bisphosphate (PIP(2)) along with sn-1,2-diacylglycerol, and both of these are important cardiac effectors. Therefore, to evaluate the functional importance of Ins(1,4,5)P(3) in cardiomyocytes (NRVM), we overexpressed IP(3) 5-phosphatase to increase degradation. Overexpression of IP(3) 5-phosphatase reduced Ins(1,4,5)P(3) responses to alpha(1)-adrenergic receptor agonists acutely, but with longer stimulation, caused an overall increase in phospholipase C (PLC) activity, associated with a selective increase in expression of PLCbeta1, that served to normalise Ins(1,4,5)P(3) content. Similar increases in PLC activity and PLCbeta1 expression were observed when Ins(1,4,5)P(3) was sequestered onto the PH domain of PLCdelta1, a high affinity selective Ins(1,4,5)P(3)-binding motif. These findings suggested that the available level of Ins(1,4,5)P(3) selectively regulates the expression of PLCbeta1. Cardiac responses to Ins(1,4,5)P(3) are mediated by type 2 IP(3)-receptors. Hearts from IP(3)-receptor (type 2) knock-out mice showed heightened PLCbeta1 expression. We conclude that Ins(1,4,5)P(3) and IP(3)-receptor (type 2) regulate PLCbeta1 and thereby maintain levels of Ins(1,4,5)P(3). This implies some functional significance for Ins(1,4,5)P(3) in the heart.
authors.affiliation: Cellular Biochemistry Laboratory, Baker Heart Research Institute, 75 Commercial Road, Melbourne, 3004, Victoria, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vasilevski
authors.forename: David R
authors.initials: DR
authors.lastname: Grubb
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Filtz
authors.forename: Sundy
authors.initials: S
authors.lastname: Yang
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: McLeod-Dryden
authors.forename: Jieting
authors.initials: J
authors.lastname: Luo
authors.forename: Divya
authors.initials: D
authors.lastname: Karna
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D015971:Gene Expression Regulation, Enzymologic; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology*; D054799:Phospholipase C beta / Q000096:biosynthesis* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015544:Inositol 1,4,5-Trisphosphate; D054799:Phospholipase C beta