Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6595-600. doi: 10.1073/pnas.1301909110. Epub 2013 Apr 1.

Stoichiometry for drug potentiation of a pentameric ion channel.

Author information

1
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. dacosta.corrie@mayo.edu

Abstract

Drug modulation of ion channels is a powerful means to alter physiological responses for therapeutic benefit, yet the structural bases of modulation remain poorly understood. Here we study potentiation of nicotinic α7 acetylcholine receptors, which are emerging drug targets in several neurological disorders. α7 receptors are ligand-gated ion channels composed of five identical subunits, each bearing a site for the potentiating drug PNU-120596 (PNU). How the individual subunits contribute to PNU potentiation is not known. Taking advantage of a PNU-resistant mutant, we generated receptors composed of normal and PNU-resistant subunits and tagged one of the subunits with conductance mutations to report subunit stoichiometry. We then used patch clamp recording to monitor PNU potentiation of single α7 receptors with defined stoichiometry in real time. We find that potentiation depends steeply on the number of PNU-resistant subunits and that four, and possibly five, subunits must be sensitive to PNU for potentiation to occur. Thus, by monitoring the activity of every possible subunit combination, our findings predict that at the macroscopic level, PNU potentiation is highly cooperative.

PMID:
23576748
PMCID:
PMC3631634
DOI:
10.1073/pnas.1301909110
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center