Vol. 287, Issue 2, 469-479, November 1998

Determinants of Channel Gating Located in the N-Terminal Extracellular Domain of Nicotinic 7 Receptor¹

René Anand, Mark E. Nelson, Volodymyr Gerzanich, Gregg B. Wells and Jon Lindstrom

Neuroscience Center of Excellence and Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans, Louisiana 70112 (R.A.); Department of Neurosurgery, University of Maryland, MTSF, Baltimore, Maryland 21201 (V.G.); and Department of Neuroscience (M.E.N., J.L.) and Department of Pathology and Laboratory Medicine (G.B.W.), University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-6074

We identified regions within the N-terminal extracellular domain of 7 nicotinic acetylcholine receptors that affect channel gating. By single-channel analysis of 7 nicotinic acetylcholine receptors currents, we show that the difference in efficacy between the two agonists acetylcholine and 1,1-dimethyl-4-phenylpiperazinium (DMPP) is due to a slower channel activation rate by DMPP. The partial efficacy of DMPP was not caused by channel block or faster desensitization of 7 AChRs by DMPP. In addition, the efficacy and, by inference, the activation rate were found to be voltage dependent. Using chimeras of the two closely related subunits 7 and 8, we map residues that affect channel activation rate and agonist affinity to two different regions of the extracellular domain. Residues that affect channel activation rate are within the sequence 1-179, whereas residues that affect agonist affinity are within the sequence 180-208.