Multiple determinants of dihydro-β-erythroidine sensitivity on rat neuronal nicotinic receptor α subunits

Scott C. Harvey, Floyd N. Maddox, Charles W. Luetje

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

Neuronal nicotinic acetylcholine receptors are differentially sensitive to blockade by the competitive antagonist dihydro-β-erythroidine. Both α and β subunits participate in determining sensitivity to this antagonist. The α subunit contribution to dihydro-β-erythroidine sensitivity is illustrated by comparing the α4β4 receptor and the α3β4 receptor, which differ in sensitivity to dihydro-β-erythroidine by ~120-fold. IC50 values for blocking α4β4 and α3β4, responding to EC20 concentrations of acetylcholine, were 0.19 ± 0.06 and 23.1 ± 10.2 μM, respectively. To map the sequence segments responsible for this difference, we constructed a series of chimeric α subunits containing portions of the α4 and α3 subunits. These chimeras were coexpressed with β4, allowing pharmacological characterization. We found determinants of dihydro-β-erythroidine sensitivity to be distributed throughout the N-terminal extracellular domain of the α subunit. These determinants were localized to sequence segments 1- 94, 94-152, and 195-215. Loss of determinants within segment 1-94 had the largest effect, decreasing dihydro-β-erythroidine sensitivity by 4.3-fold.

Original languageEnglish (US)
Pages (from-to)1953-1959
Number of pages7
JournalJournal of neurochemistry
Volume67
Issue number5
DOIs
StatePublished - Nov 1996

Keywords

  • Acetylcholine
  • Chimera
  • Competitive antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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