Activation of neuronal alpha7 nicotinic receptors with different number of agonist binding sites

NATALIA ANDERSEN; JEREMÍAS CORRADI; STEVEN M SINE; CECILIA BOUZAT

Huerta Grande, Córdoba

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

Sociedad Argentina de Neurociencias

Neuronal  a7 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.  a7 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 a7 operates at these physiological conditions. To assess function of a7 when neurotransmitter occupies fewer than five binding sites, we generated  a7 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  a7, we found that openchannel lifetime of a receptor formed by the extracellular domain of  a7 and the transmembrane region of 5-HT3A (a7-5HT3A) 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  a7  to  volume  transmission,  a  prevalent  mechanism  of  ACh-mediated  signaling  in  the nervous system and non-neuronal cells.