Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling

Matthew J. Mahon, Mark Donowitz, C. Chris Yun, Gino V. Segre

Research output: Contribution to journalArticle

Abstract

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 cyclase1-5. 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 Cβ1 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 Cβ and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (Gi/o proteins). NHERF-mediated assembly of PTH1R and phospholipase Cβ 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.

Original languageEnglish (US)
Pages (from-to)858-861
Number of pages4
JournalNature
Volume417
Issue number6891
DOIs
StatePublished - Jun 20 2002

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Parathyroid Hormone Receptor Type 1
Type C Phospholipases
G-Protein-Coupled Receptors
Adenylyl Cyclases
Proteins
Gi-Go GTP-Binding Protein alpha Subunits
Hormones
PDZ Domains
Skeleton
sodium-hydrogen exchanger regulatory factor
Cell Membrane

ASJC Scopus subject areas

  • General

Cite this

Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. / Mahon, Matthew J.; Donowitz, Mark; Yun, C. Chris; Segre, Gino V.

In: Nature, Vol. 417, No. 6891, 20.06.2002, p. 858-861.

Research output: Contribution to journalArticle

Mahon, Matthew J. ; Donowitz, Mark ; Yun, C. Chris ; Segre, Gino V. / Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. In: Nature. 2002 ; Vol. 417, No. 6891. pp. 858-861.
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