Beyond the Channel: Metabotropic Signaling by Nicotinic Receptors

The alpha 7 nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel (LGIC) that plays an important role in cellular calcium signaling and contributes to several neurological diseases. Agonist binding to the alpha 7 nAChR induces fast channel activation followed by inactivation and prolonged desensitization while triggering long-lasting calcium signaling. These activities foster neurotransmitter release, synaptic plasticity, and somatodendritic regulation in the brain. We discuss here the ability of alpha 7 nAChRs to operate in ionotropic (alpha 7(i)) and metabotropic (alpha 7(m)) modes, leading to calcium-induced calcium release (CICR) and G protein-associated inositol trisphosphate (IP3)-induced calcium release (IICR), respectively. Metabotropic activity extends the spatial and temporal aspects of calcium signaling by the alpha 7 channel beyond its ionotropic limits, persisting into the desensitized state. Delineation of the ionotropic and metabotropic properties of the alpha 7 nAChR will provide definitive indicators of moment-to-moment receptor functional status that will, in turn, spearhead new drug development.