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Am J Physiol Gastrointest Liver Physiol 284: G472-G480, 2003; doi:10.1152/ajpgi.00345.2002
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Vol. 284, Issue 3, G472-G480, March 2003

Erk1/2- and p38 MAP kinase-dependent phosphorylation and activation of cPLA2 by m3 and m2 receptors

Huiping Zhou, Sankar Das, and Karnam S. Murthy

Departments of Physiology and Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298

This study examined the upstream signaling pathways initiated by muscarinic m2 and m3 receptors that mediate sustained ERK1/2- and p38 MAP kinase-dependent phosphorylation and activation of the 85-kDa cytosolic phospholipase (cPL)A2 in smooth muscle. The pathway initiated by m2 receptors involved sequential activation of Gbeta gamma i3, phosphatidylinositol (PI)3-kinase, Cdc42, and Rac1, p21-activated kinase (PAK1), p38 mitogen-activated protein (MAP) kinase, and cPLA2, and phosphorylation of cPLA2 at Ser505. cPLA2 activity was inhibited to the same extent (61 ± 5 to 72 ± 4%) by the m2 antagonist methoctramine, Gbeta antibody, pertussis toxin, the PI3-kinase inhibitor LY 294002, PAK1 antibody, the p38 MAP kinase inhibitor SB-203580, and a Cdc42/Rac1 GEF (Vav2) antibody and by coexpression of dominant-negative Cdc42 and Rac1 mutants. The pathway initiated by m3 receptors involved sequential activation of Galpha q, PLC-beta 1, PKC, ERK1/2, and cPLA2, and phosphorylation of cPLA2 at Ser505. cPLA2 activity was inhibited to the same extent (35 ± 3 to 41 ± 5%) by the m3 antagonist 4-diphenylacetoxy-N-methylpiperdine (4-DAMP), the phosphoinositide hydrolysis inhibitor U-73122, the PKC inhibitor bisindolylmaleimide, and the ERK1/2 inhibitor PD 98059. cPLA2 activity was not affected in cells coexpressing dominant-negative RhoA and PLC-delta 1 mutants, implying that PKC was not derived from phosphatidylcholine hydrolysis. The effects of ERK1/2 and p38 MAP kinase on cPLA2 activity were additive and accounted fully for activation and phosphorylation of cPLA2.

cytosolic phospholipase A2; cytosolic phospholipase A2 phosphorylation; muscarinic receptors.


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