Heteromeric complexes of α5 and/or α7 subunits -: Effects of calcium and potential role in nicotine-induced presynaptic facilitation

Nicotine alters a broad spectrum of behaviors, including attention, arousal, anxiety, and memory. The cellular physiology of nicotine is comparably diverse: nicotine interacts with an array of ionotropic receptors whose gating can lead to direct depolarization of neurons or to an indirect modulation of neuronal excitability by presynaptic facilitation. Furthermore, as many laboratories have shown, the alpha- and beta-type subunits that comprise neuronal nicotinic acetylcholine receptors (nAChRs) are encoded by multiple, homologous genes, yielding at least seven alpha and three beta subunits, distinct in primary sequence. nAChRs that differ in subunit composition differ in pharmacology, conductance, and kinetics as well as in their permeability to and modulation by calcium. We will first discuss recent studies on the biophysics of a special (peculiar?) subset of nAChRs, focusing on heteromeric nAChRs comprised of alpha 4 beta 2 +/- alpha 5 or alpha 7 +/- beta 2 and alpha 5. These nAChR channel subtypes are potently and differentially modulated by changes in intracellular calcium ([Ca]). Thus, the P-o, tau(o), and desensitization kinetics of alpha 4 beta 2 channels are altered by changes in [Ca](int) from 0 to 50 mu M; nAChRs that include the alpha 5 subunit are oppositely regulated. Mutagenesis of specific residues within the M1 to M2 domain of alpha 4, beta 2, and alpha 5 suggest a possible Ca binding "pocket." The assembly of functional nAChRs that include alpha 5 and/or alpha 7 and the potential role of these novel heteromeric complexes in presynaptic facilitation will also be presented.