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.