Stoichiometry for activation of neuronal alpha7 nicotinic receptors

NATALIA ANDERSEN; JEREMÍAS CORRADI; STEVEN SINE; CECILIA BOUZAT

Huerta Grande, Cordoba.

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2013

Sociedad Argentina de Investigación en Neurociencias (SAN)

Neuronal alpha7 nicotinic receptors are homopentameric ligand-gated ion channels (LGICs) that participate in cognition, synaptic plasticity and neuroprotection, and have emerged as therapeutic targets for treatment of neurological disorders. Alpha7 often localizes distal to sites of nerve-released ACh, binds ACh with low affinity, and thus elicits its biological response with partial occupancy of its five identical binding sites. We therefore addressed the question of how alpha7 operates at these physiological conditions. To assess function of alpha7 when neurotransmitter occupies fewer than five binding sites, we generated alpha7 receptors with a different number of functional neurotransmitter binding sites. By measuring open-channel lifetime of individual receptors, we found that only one occupied site allows maximal response and that the additional sites allow enhanced agonist sensitivity. In contrast to alpha7, we found that open-channel lifetime of a receptor formed by the extracellular domain of alpha7 and the transmembrane region of 5-HT3A (alpha7-5HT3A) is dependent on the number of functional binding sites. Our results reveal that: i) the agonist binding domain is not sufficient to determine the relationship between agonist occupancy and open-channel stability and, ii) the distinctive ability of a single occupancy to elicit a full biological response adapts alpha7 to volume transmission, a prevalent mechanism of ACh-mediated signaling in the nervous system and non-neuronal cells.