Functional interactions between the extracellular domain and the seven-transmembrane domain in Ca 2+ receptor activation

O. M. Hauache, J. Hu, K. Ray, Allen M. Spiegel

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

We studied the activity of mutants involving the amino-terminal extracellular, seven-transmembrane (7TM) and carboxy-terminal tail domains of the human Ca 2+ receptor to gain insight into the functional interactions between these domains during receptor activation. Missense mutations of highly conserved residues, D190 and E297, in the extracellular domain (ECD), and a mutation within part of the proximal carboxy-terminal tail, A877-880E, resulted in receptors with severely reduced response to Ca 2+ despite adequate cell surface expression. Coexpression of either D190A or E297K mutants with A877-880E led to significant reconstitution of function. No such reconstitution occurred when D190A or E297K mutants were coexpressed with a truncation mutant possessing an intact amino-terminal extracellular and first transmembrane domain, despite evidence for heterodimerization and cell surface expression of the respective mutant receptors. In addition, no reconstitution of function was observed when D190A was coexpressed with a deletion Ca 2+ receptor mutant lacking only a cysteinerich region located in the ECD of the Ca 2+ receptor (Ca-//-Ca). Moreover, coexpression of this Ca-//-Ca with A877-880E did not recover function. The results show that Ca 2+ receptor extracellular and 7TM domains are discrete entities that can communicate within the context of a heterodimer composed of complementary mutant receptors. Two intact 7TM domains and two intact cysteine-rich regions appear to be required for such communication to occur. The results are discussed in the context of a speculative model of receptor structure and function.

Original languageEnglish (US)
Pages (from-to)63-70
Number of pages8
JournalEndocrine
Volume13
Issue number1
StatePublished - 2000
Externally publishedYes

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Tail
Missense Mutation
Cysteine
Communication
Mutation

Keywords

  • Activation
  • Calcium receptor
  • Functional interations

ASJC Scopus subject areas

  • Endocrinology

Cite this

Functional interactions between the extracellular domain and the seven-transmembrane domain in Ca 2+ receptor activation. / Hauache, O. M.; Hu, J.; Ray, K.; Spiegel, Allen M.

In: Endocrine, Vol. 13, No. 1, 2000, p. 63-70.

Research output: Contribution to journalArticle

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