Ins(1,4,5)P3 regulates phospholipase Cβ1 expression in cardiomyocytes

The functional significance of the Ca2+-releasing second messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P3, IP3) in the heart has been controversial. Ins(1,4,5)P3 is generated from the precursor lipid phosphatidylinositol(4,5)bisphosphate (PIP2) 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)P3 in cardiomyocytes (NRVM), we overexpressed IP3 5-phosphatase to increase degradation. Overexpression of IP3 5-phosphatase reduced Ins(1,4,5)P3 responses to α1-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 PLCβ1, that served to normalise Ins(1,4,5)P3 content. Similar increases in PLC activity and PLCβ1 expression were observed when Ins(1,4,5)P3 was sequestered onto the PH domain of PLCδ1, a high affinity selective Ins(1,4,5)P3-binding motif. These findings suggested that the available level of Ins(1,4,5)P3 selectively regulates the expression of PLCβ1. Cardiac responses to Ins(1,4,5)P3 are mediated by type 2 IP3-receptors. Hearts from IP3-receptor (type 2) knock-out mice showed heightened PLCβ1 expression. We conclude that Ins(1,4,5)P3 and IP3-receptor (type 2) regulate PLCβ1 and thereby maintain levels of Ins(1,4,5)P3. This implies some functional significance for Ins(1,4,5)P3 in the heart.