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XLα s is a novel activator of PLCβ4
Author(s) -
Phan Hoa,
Loomis Joseph,
Bastepe Murat,
He Qing,
Smrcka Alan
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03060
Subject(s) - gq alpha subunit , phospholipase c , diacylglycerol kinase , second messenger system , g protein , microbiology and biotechnology , activator (genetics) , phosphatidylinositol , inositol , g protein coupled receptor , signal transduction , pleckstrin homology domain , biology , effector , c2 domain , gtp' , protein kinase c , biochemistry , receptor , enzyme , membrane
Phospholipase C (PLC) enzymes are essential for normal cellular function. Upon stimulation by GPCRs or RTKs, PLCs hydrolyze phosphatidylinositol 4,5‐bisphosphate (PIP 2 ) at cell membranes to generate diacylglycerol (DAG) and inositol 1,4,5‐trisphosphate (IP 3 ). DAG and IP 3 are important second messengers in signal transduction. DAG regulates activity of protein kinase C and IP 3 mobilizes intracellular Ca 2+ , which initiate multiple signaling cascades and cellular processes. Dysregulation of PLC function gives rise to pathological processes. Among six mammalian PLC subfamilies, PLCβ isozymes are activated by Gα q , Gβγ, small G proteins and thus, play significant roles in various cellular activities. Extra‐large stimulatory Gα (XLα s ) is a large variant of Gα s . Biochemically, XLα s activation by GPCR mediates cAMP generation similarly to Gα s , however, Gα s andXLα s have distinct cellular and physiological functions. He et al. suggests that XLα s is able to stimulate IP 3 signaling in vivo . In this study, we aim to identify the PLC that mediates this phenomenon. By co‐expressing XLα s with different PLC constructs in cells and measuring total IP production, we identify that XLα s stimulates PLCβ4 to generate IP 3 . This activity is specific to XLα s because wild‐type and constitutively active Gα s do not activate PLCβ4. Using purified proteins, we show that XLα s directly and specifically activates PLCβ4. Interestingly, unlike Gα q , XLα s does not require GTP to activate its effector PLCβ4. We also identify that the helical domain preceding the nucleotide‐binding domain in XLα s is required for its ability to stimulate PLCβ4. Further studies are underway to determine the mode of activation of PLCβ4 by XLα s and the role of XLα s – mediated stimulation of PLCβ4 in physiological systems. Overall, we identify XLα s as a novel direct activator of PLCβ4 and this novel signaling axis potentially play important roles physiologically.