Conserved motifs in somatostatin, D2-dopamine, and alpha 2B-adrenergic receptors for inhibiting the Na-H exchanger, NHE1.
Receptor subtypes within families of G protein-coupled receptors that are activated by similar ligands can regulate distinct intracellular effectors. We identified conserved motifs within intracellular domains 2 and 3 of selective subtypes of several G protein-coupled receptor families that confer coupling to the Na-H exchanger, NHE1. A T(s,p)V motif within intracellular domain 2 and a QQ(r) motif within intracellular domain 3 are shared by the somatostatin receptor subtypes SSTR1, -3, and -4, which couple to the inhibition of NHE1, but not by SSTR2 and -5, which do not signal to NHE1. Only the collective substitution of cognate SSTR2 residues with these two motifs conferred the ability of mutant SSTR2 to inhibit NHE1. Both motifs are present in D(2)-dopamine receptors, which inhibit NHE1, and in alpha(2B)-adrenergic receptors, which couple to the inhibition of NHE1, but not in alpha(2A)-adrenergic receptors, which do not regulate NHE1. These findings indicate that motifs shared by different subfamilies of G protein-coupled receptors, but not necessarily by receptor subtypes within a subfamily, can confer coupling to a common effector.
Lin
Chin-Yu
CY
University of California, San Francisco, San Francisco, California 94143, USA.
Varma
Madhulika G
MG
Joubel
Anita
A
Madabushi
Srinivasan
S
Lichtarge
Olivier
O
Barber
Diane L
DL
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D008565:Membrane Proteins; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008565:Membrane Proteins; D018341:Receptors, Adrenergic, alpha-2; D011956:Receptors, Cell Surface; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C103631:somatostatin receptor 3; C098681:somatostatin receptor subtype-4