Heteromeric Complexes of α5 and/or α7 Subunits: Effects of Calcium and Potential Role in Nicotine‐Induced Presynaptic Facilitation

Abstract

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 Po, tau o, and desensitization kinetics of alpha 4 beta 2 channels are altered by changes in [Ca]int from 0 to 50 microM; nAChRs that include the alpha 5 subunit are oppositely regulated. Mutagenesis of specific residues within the M1 and 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.

The α7 Nicotinic Acetylcholine Receptor Subunit Exists in Two Isoforms that Contribute to Functional Ligand-Gated Ion Channels

“…Although several reports support the coassembly of ␣7 with other subunits expressed in mammals, such as ␣5, ␤2, and ␤3 (Girod et al, 1999;Khiroug et al, 2002), various studies using subunit-specific antibodies failed to detect the presence of non-␣7 subunits in native ␣7-nAChRs (Schoepfer et al, 1990;Vernallis et al, 1993;Chen and Patrick, 1997;Drisdel and Green, 2000). In addition, the conventional ␣7 gene product, ␣7-1, forms functional homomeric channels when expressed in exogenous systems such as X. laevis oocytes and SH-EP1 cells (Couturier et al, 1990;Seguela et al, 1993;Peng et al, 1999).…”

Cholinergic interneuron characteristics and nicotinic properties in the striatum

“…In the third classification, only the ␣7 subunit is widely distributed in the mammalian central nervous system. This classification scheme is not perfect because there is evidence that subunits from the separate classes are capable of combining to form nAChRs, but those combinations in most cases may be relatively rare in biology (Girod et al, 1999). Based on evidence gained from the heterologous expression of nAChR subunits, the following conclusion can be drawn: a limited number of subunit combinations are favored, but more rare combinations are possible.…”

Structural and functional diversity of native brain neuronal nicotinic receptors

“…For example, the α7 subtype is mainly a homomeric receptor in neurons that co-express other subunits, but can form heteromeric receptors made up of the α7 subunit with the β3, α5 and β3 subunits in heterologous expression systems [41, 54,55]. …”