Csk mediates G-protein-coupled lysophosphatidic acid receptor-induced inhibition of membrane-bound guanylyl cyclase activity.
Natriuretic peptides (NPs) are involved in many physiological processes, including the regulation of vascular tone, sodium excretion, pressure-volume homeostasis, inflammatory responses, and cellular growth. The two main receptors of NP, membrane-bound guanylyl cyclases A and B (GC-A and GC-B), mediate the effects of NPs via the generation of cGMP. NP-stimulated generation of cGMP can be modulated by intracellular processes, whose exact nature remains to be elucidated. Thus, serum and lysophosphatidic acid (LPA), by unknown pathways, have been shown to inhibit the NP-induced generation of cGMP. Here we report that the nonreceptor-tyrosine-kinase Csk is an essential component of the intracellular modulation of atrial natriuretic peptide (ANP)-stimulated activation of GC-A. The genetic deletion of Csk (Csk(-)(/)(-)) in mouse embryonic fibroblasts blocked the inhibitory effect of both serum and LPA on the ANP-stimulated generation of cGMP. Moreover, using a chemical rescue approach, we also demonstrate that the catalytic activity of Csk is required for its modulatory function. Our data demonstrate that Csk is involved in the control of cGMP levels and that membrane-bound guanylyl cyclases can be critically modulated by other receptor-initiated intracellular signaling pathways.
Madhusoodanan
K S
KS
Department of Physiology, Cornell University, Weill Medical College, New York, New York 10021, USA.
Guo
Dagang
D
McGarrigle
Deirdre K
DK
Maack
Thomas
T
Huang
Xin-Yun
XY
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002384:Catalysis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D014162:Transfection; D019061:src-Family Kinases
D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D013912:Threonine; D012694:Serine; D009320:Atrial Natriuretic Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C032881:lysophosphatidic acid