Coupling of endothelin receptors to the ERK/MAP kinase pathway

Abstract

Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ET A and ET B . To address the role of post-translational ET receptor modifications such as acylation on ERK activation and to identify relevant downstream effectors coupling the ET receptor to the ERK signaling cascades we have constructed a panel of palmitoylation-deficient ET receptor mutants with differential Ga protein binding capacity. Endothelin-1 stimulation of wild-type ET A or ET B induced a fivefold to sixfold increase in ERK in COS-7 and CHO cells whereas fulllength nonpalmitoylated ET A and ET B mutants failed to stimulate ERK. A truncated ET B lacking the C-terminal tail domain including putative phosphorylation and arrestin binding site(s) but retaining the critical palmitoylation site(s) was still able to fully stimulate ERK activation. Using mutated ET receptors with selective G-protein-coupling we found that endothelin-induced stimulation of Ga q , but not of

Palmitoylation of the Human Prostacyclin Receptor

“…For example, the ␤ 2 -adrenergic receptor (AR) is palmitoylated at Cys 341 , and palmitoylation at this site is required for ␤ 2 -AR coupling to adenylyl cyclase (9) and is increased upon exposure of cells to agonist (10). Palmitoylation of the endothelin (ET) A and ET B receptors is required for their coupling to the extracellular signal regulated kinase/ mitogen-activated protein kinase cascade (11). Mutation of Cys 442 within the C-tail of the ␣ 2A -AR receptor inhibits receptor down-regulation in response to prolonged agonist exposure (12).…”

Recombinase-mediated cassette exchange reveals the selective use of Gq/G11-dependent and -independent endothelin 1/endothelin type A receptor signaling in pharyngeal arch development

“…Knock-in of Ednrb cDNA could only partially rescue the Ednra-null phenotype Previous studies have demonstrated that Edn1 can bind to both Ednra and Ednrb receptors with similar affinities and activate common signaling pathways, including G q /G 11 -dependent signals in many cells (Cramer et al, 2001;Jouneaux et al, 1994;Kedzierski and Yanagisawa, 2001;Masaki et al, 1999;Takigawa et al, 1995). If Ednra and Ednrb are interchangeable in the context of pharyngeal arch development, Ednrb knock-in is expected to rescue the Ednranull phenotype.…”

Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: Comparison with interleukin‐1β in normal and scleroderma dermal fibroblasts

“…Coupling of ET-1 receptors to G␣q could lead to activation of phospholipase C and hence PKC (8,31,32). The results of PKC inhibition experiments using bisindolylmaleimide I suggested involvement of a novel PKC subtype ( Figure 6A), and the lack of effect of Rottlerin highlighted a possible role of PKC ( Figure 6B).…”