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The Journal of Neuroscience, January 15, 2000, 20(2):529-541

A Molecular Link between Inward Rectification and Calcium Permeability of Neuronal Nicotinic Acetylcholine 34 and 42 Receptors

Ali Pejmun Haghighi and Ellis Cooper

Department of Physiology, McGill University, Montréal, Québec, Canada H3G 1Y6

Many nicotinic acetylcholine receptors (nAChRs) expressed by central neurons are located at presynaptic nerve terminals. These receptors have high calcium permeability and exhibit strong inward rectification, two important physiological features that enable them to facilitate transmitter release. Previously, we showed that intracellular polyamines act as gating molecules to block neuronal nAChRs in a voltage-dependent manner, leading to inward rectification. Our goal is to identify the structural determinants that underlie the block by intracellular polyamines and govern calcium permeability of neuronal nAChRs. We hypothesize that two ring-like collections of negatively charged amino acids (cytoplasmic and intermediate rings) near the intracellular mouth of the pore mediate the interaction with intracellular polyamines and also influence calcium permeability. Using site-directed mutagenesis and electrophysiology on ₄₂ and ₃₄ receptors expressed in Xenopus oocytes, we observed that removing the five negative charges of the cytoplasmic ring had little effect on either inward rectification or calcium permeability. However, partial removal of negative charges of the intermediate ring diminished the high-affinity, voltage-dependent interaction between intracellular polyamines and the receptor, abolishing inward rectification. In addition, these nonrectifying mutant receptors showed a drastic reduction in calcium permeability. Our results indicate that the negatively charged glutamic acid residues at the intermediate ring form both a high-affinity binding site for intracellular polyamines and a selectivity filter for inflowing calcium ions; that is, a common site links inward rectification and calcium permeability of neuronal nAChRs. Physiologically, this molecular mechanism provides insight into how presynaptic nAChRs act to influence transmitter release.

Key words: nicotinic acetylcholine receptor; presynaptic receptors; transmitter release; ion permeation; gating particles

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Copyright © 2000 Society for Neuroscience  0270-6474/00/202529-13$05.00/0

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