nAChRs are excitatory neurotransmitter-gated ion channels that belong to a superfamily that includes other ionotropic receptors for 5-HT, glycine, and GABA. This family of receptors is comprised of 16 different subunits in humans (α1 -7, α9-10, β1-4, δ, ε, γ). This wide variety of subtypes of nAChRs arising from combinations of subunits displays a range of different functional and pharmacological Inhibitors,research,lifescience,medical properties. Neuronal nAChRs are assembled from five transmembrane subunits that are arranged around a central water-filled pore. Neuronal

subunits that form nAChRs in αβ combinations include α2-α6 and β2-β4. Although most nAChRs subunits assemble only into heteropentameric receptor ion channel combinations, the α7 subunits are able to generate functional homomeric nAChRs.209 nAChRs composed of α4β2 and α7 subunits make up the majority of the nAChRs in the brain. There are two ACh binding sites per receptor. Mammalian nAChRs are cation-selective, being permeable to small monovalent and divalent cations like Ca2+. Nicotinic receptor activity causes depolarization, Inhibitors,research,lifescience,medical and the divalent cation permeability plays an important physiological role by supplying ionic signals, including Ca2+. α7nAChRs α7 nAChRs are abundantly expressed in the hippocampus and cortex. They have distinct characteristics due to their homopentameric composition

that distinguishes them from the other nAChR Inhibitors,research,lifescience,medical subtypes. α7 nAChRs are rapidly desensitizing, are an order of magnitude less sensitive to nicotine as an agonist, and have a higher calcium permeability than other nAChRs.209 Because cholinergic innervation arises from projections that send diffuse afferents to a broad range of brain areas, nicotinic activity is a modulatory Inhibitors,research,lifescience,medical signal that subtly influences many neurotransmitter systems and contributes to the overall efficiency of various neural Inhibitors,research,lifescience,medical circuits. Cholinergic fibers innervate the entire hippocampus with synaptic contacts made onto granule cells,

pyramidal cells, interneurons, and neurons of the hilus.210 The hippocampus expresses a wide variety of nAChR subunits, but the α7, α4, and β2 subunits predominate. The GABAergic interneurons more densely express nAChRs than do the glutamatergic cells. Activation of a7nAChRs on presynaptic terminals Selleck Oligomycin A of glutamatergic pyramidal neurons increases intraterminal Ca2+ levels to facilitate glutamate release.211 α7nAChRs are also present in high density at postsynaptic sites on PV+-GABAergic interneurons212 that are vulnerable in schizophrenia,130 where they ITF2357 in vitro mediate fast cholinergic excitatory transmission.213 In the cortex, cholinergic innervation sparsely reaches all layers, but layer V is the most heavily innervated, especially in the motor and sensory areas. The manner in which nicotinic signaling affects cortical activity is dependent on which part of the pyramidal cell the nAChRs are activated.