Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling.
The parathyroid hormone 1 receptor (PTH1R) is a class II G-protein-coupled receptor. PTH1R agonists include both PTH, a hormone that regulates blood calcium and phosphate, and PTH-related protein (PTHrP), a paracrine/autocrine factor that is essential for development, particularly of the skeleton. Adenylyl cyclase activation is thought to be responsible for most cellular responses to PTH and PTHrP, although many actions appear to be independent of adenylyl cyclase. Here we show that the PTH1R binds to Na(+)/H(+) exchanger regulatory factors (NHERF) 1 and 2 through a PDZ-domain interaction in vitro and in PTH target cells. NHERF2 simultaneously binds phospholipase C beta 1 and an atypical, carboxyl-terminal PDZ consensus motif, ETVM, of the PTH1R through PDZ1 and PDZ2, respectively. PTH treatment of cells that express the NHERF2 PTH1R complex markedly activates phospholipase C beta and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (G(i/o) proteins). NHERF-mediated assembly of PTH1R and phospholipase C beta is a unique mechanism to regulate PTH signalling in cells and membranes of polarized cells that express NHERF, which may account for many tissue- and cell-specific actions of PTH/PTHrP and may also be relevant to signalling by many G-protein-coupled receptors.
Mahon
Matthew J
MJ
Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Donowitz
Mark
M
Yun
C Chris
CC
Segre
Gino V
GV
D037361:Adenylate Cyclase Toxin; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney; D010281:Parathyroid Hormone / Q000494:pharmacology*; D054799:Phospholipase C beta; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers; D013379:Substrate Specificity; D020798:Two-Hybrid System Techniques; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D007295:Inositol Phosphates; D007527:Isoenzymes; D010281:Parathyroid Hormone; D010750:Phosphoproteins; D018016:Receptors, Parathyroid Hormone; D017923:Sodium-Hydrogen Exchangers; D010566:Virulence Factors, Bordetella; C093376:sodium-hydrogen exchanger regulatory factor; D000242:Cyclic AMP; D010738:Type C Phospholipases; C518033:PLCB1 protein, human; D054799:Phospholipase C beta; C518035:Plcb1 protein, rat