Stoichiometry for activation of neuronal alpha7 nicotinic receptors.

ANDERSEN NATALIA; CORRADI JEREMIAS; SINE STEVEN; BOUZAT C

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2013 vol. 110 p. 20819 - 20824

0027-8424

Neuronal 7 nicotinic receptors elicit rapid cation influx in response to acetylcholine (ACh) or its hydrolysis product choline. They contribute to cognition, synaptic plasticity, and neuroprotection, and have been implicated in neurodegenerative and neuropsychiatric disorders. 7, however, often localizes distal to sites of nerve-released ACh, binds ACh with low affinity, and thus elicits its biological response with low agonist occupancy. To assess function of 7 when ACh occupies fewer than five of its identical binding sites, we measured open-channel lifetime of individual receptors in which four of the five ACh binding-sites were disabled. To improve time resolution of the inherently brief 7 channel openings, background mutations or a potentiator were used to increase open duration. We find that in receptors with only one intact binding site, open-channel lifetime is indistinguishable from receptors with five intact binding sites, counter to expectations from prototypical neurotransmitter-gated ion channels where open-channel lifetime increases with the number of binding sites occupied by agonist. Replacing the membrane-embedded domain of 7 by that of the related 5-HT3A receptor increases the number of sites that need to be occupied to achieve maximal open-channel lifetime, thus revealing a novel interdependence between the detector and actuator domains of these receptors. The distinctive ability of a single occupancy to elicit a full biological response adapts 7 to volume transmission, a prevalent mechanism of ACh-mediated signaling in the nervous system and non-neuronal cells.