The hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C (PLC) is a critical early step in the regulation of various cell functions by extracellular signaling molecules. This reaction produces diacylglycerol and inositol 1,4,5-trisphosphate, which mediate the activation of protein kinase C (PKC) and intracellular Ca2+ release, respectively. PIP2 also modulates several protein activities and serves as a cofactor for phosphatidylcholine-specific phospholipase D (PLD) and a substrate for phosphoinositide 3-kinase (PI 3-kinase). The activity of PLC is tightly regulated through multiple mechanisms that link PLC isoforms to various receptors. PLC isoforms are divided into three types: β, γ, and δ. The δ-type isoforms are smaller than the β- and γ-type isoforms. The catalytic domain of PLC consists of two regions of high sequence homology (X and Y), and all PLCs contain a PH domain. The three-dimensional structure of PLC-δ1 reveals that the X and Y regions are tightly associated, with accessory modules like the EF-hand and C2 domains. Calcium is essential for the function of the C2 domain, which mediates Ca2+-dependent binding to lipid vesicles. The multidomain structure of PLC-δ1 is likely common to all mammalian PLC isoforms, with additional regulatory COOH-terminal and SH domains in PLC-β and PLC-γ, respectively. Gqα subunits of heterotrimeric G proteins activate PLC-β isoforms but not PLC-γ1 or PLC-δ1. The GTPγS-activated Gαq or Gα11 subunits stimulate PLC-β isoforms with varying potencies. The Gβγ dimer also activates PLC-β isozymes, with PLC-β3 being the most sensitive. The COOH-terminal region of PLC-β1 is essential for activation by Gβγ. Polypeptide growth factors induce PIP2 turnover by activating PLC-γ through receptor-mediated tyrosine phosphorylation. Receptor autophosphorylation creates high-affinity binding sites for SH2 domain-containing proteins, including PLC-γ1. Nonreceptor protein tyrosine kinases (PTKs) also activate PLC-γ isozymes in response to the ligation of certain cell surface receptors. PLC-γ isozymes can be activated directly by lipid-derived second messengers such as phosphatidic acid and arachidonic acid, without tyrosine phosphorylation. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) generated by PI 3-kinase also activates PLC-γ isozymes. The mechanism by which PLC-δ isThe hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C (PLC) is a critical early step in the regulation of various cell functions by extracellular signaling molecules. This reaction produces diacylglycerol and inositol 1,4,5-trisphosphate, which mediate the activation of protein kinase C (PKC) and intracellular Ca2+ release, respectively. PIP2 also modulates several protein activities and serves as a cofactor for phosphatidylcholine-specific phospholipase D (PLD) and a substrate for phosphoinositide 3-kinase (PI 3-kinase). The activity of PLC is tightly regulated through multiple mechanisms that link PLC isoforms to various receptors. PLC isoforms are divided into three types: β, γ, and δ. The δ-type isoforms are smaller than the β- and γ-type isoforms. The catalytic domain of PLC consists of two regions of high sequence homology (X and Y), and all PLCs contain a PH domain. The three-dimensional structure of PLC-δ1 reveals that the X and Y regions are tightly associated, with accessory modules like the EF-hand and C2 domains. Calcium is essential for the function of the C2 domain, which mediates Ca2+-dependent binding to lipid vesicles. The multidomain structure of PLC-δ1 is likely common to all mammalian PLC isoforms, with additional regulatory COOH-terminal and SH domains in PLC-β and PLC-γ, respectively. Gqα subunits of heterotrimeric G proteins activate PLC-β isoforms but not PLC-γ1 or PLC-δ1. The GTPγS-activated Gαq or Gα11 subunits stimulate PLC-β isoforms with varying potencies. The Gβγ dimer also activates PLC-β isozymes, with PLC-β3 being the most sensitive. The COOH-terminal region of PLC-β1 is essential for activation by Gβγ. Polypeptide growth factors induce PIP2 turnover by activating PLC-γ through receptor-mediated tyrosine phosphorylation. Receptor autophosphorylation creates high-affinity binding sites for SH2 domain-containing proteins, including PLC-γ1. Nonreceptor protein tyrosine kinases (PTKs) also activate PLC-γ isozymes in response to the ligation of certain cell surface receptors. PLC-γ isozymes can be activated directly by lipid-derived second messengers such as phosphatidic acid and arachidonic acid, without tyrosine phosphorylation. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) generated by PI 3-kinase also activates PLC-γ isozymes. The mechanism by which PLC-δ is