Identification of a Zn2+-binding site on the dopamine D 2 receptor

Yong Liu, Martha M. Teeter, Curtiss J. DuRand, Kim Neve

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Zinc (II) modulates the function of many integral membrane proteins. To identify the Zn2+-binding site responsible for allosteric modulation of the D2 dopamine receptor, we first demonstrated that the binding site is likely located in extracellular loops or in transmembrane regions that are accessible from the extracellular milieu. We mutated every histidine in these regions to alanine; two mutants, H394A and H399A, exhibited a reduced response to Zn2+. Combined mutation of H394 and H399 caused a larger effect of zinc than did either single mutation. Mutation of other potential Zn2+-binding residues predicted to be in proximity to H394 or H399 did not substantially alter the potency of Zn2+. The double mutant H394A/H399A was similar to D2 in affinity for [3H] spiperone and ability to inhibit cyclic AMP accumulation. We conclude that binding of Zn2+ to H394 and H399 on the dopamine D2 receptor contributes to allosteric regulation of antagonist binding.

Original languageEnglish (US)
Pages (from-to)873-879
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume339
Issue number3
DOIs
StatePublished - Jan 20 2006

Fingerprint

Dopamine D2 Receptors
Zinc
Dopamine
Binding Sites
Spiperone
Mutation
Histidine
Allosteric Regulation
Alanine
Cyclic AMP
Membrane Proteins
Modulation

Keywords

  • Allosteric modulation
  • Dopamine D receptor
  • Site-directed mutagenesis
  • Zinc ion-binding site

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Identification of a Zn2+-binding site on the dopamine D 2 receptor. / Liu, Yong; Teeter, Martha M.; DuRand, Curtiss J.; Neve, Kim.

In: Biochemical and Biophysical Research Communications, Vol. 339, No. 3, 20.01.2006, p. 873-879.

Research output: Contribution to journalArticle

Liu, Yong ; Teeter, Martha M. ; DuRand, Curtiss J. ; Neve, Kim. / Identification of a Zn2+-binding site on the dopamine D 2 receptor. In: Biochemical and Biophysical Research Communications. 2006 ; Vol. 339, No. 3. pp. 873-879.
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