Ins(1,4,5)P(3) regulates phospholipase Cbeta1 expression in cardiomyocytes.
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.
Vasilevski
Oliver
O
Cellular Biochemistry Laboratory, Baker Heart Research Institute, 75 Commercial Road, Melbourne, 3004, Victoria, Australia.
Grubb
David R
DR
Filtz
Theresa M
TM
Yang
Sundy
S
McLeod-Dryden
Tiffany J
TJ
Luo
Jieting
J
Karna
Divya
D
Chen
Ju
J
Woodcock
Elizabeth A
EA
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
D015544:Inositol 1,4,5-Trisphosphate; D054799:Phospholipase C beta