Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology.

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (alpha2-alpha10) and three beta (beta2, beta3, and beta4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although alpha4beta2- and alpha7-nAChRs are the two major functional nAChR types in the CNS, alpha6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of alpha6*-nAChRs have been assessed with the use of alpha6 subunit blockers such as alpha-conotoxin MII and PIA, and also by using alpha6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), alpha6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, alpha6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, alpha6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of alpha6*-nAChR function, pharmacology and pathophysiology.

Nicotine modulates GABAergic transmission to dopaminergic neurons in substantia nigra pars compacta.

AIM: Dopaminergic neurons in the substantia nigra pars compacta (SNc) play important roles in motor control and drug addiction. As the major afferent, GABAergic innervation controls the activity of SNc dopaminergic neurons. Although it is clear that nicotine modulates SNc dopaminergic neurons by activating subtypes of somatodendritic nicotinic acetylcholine receptors (nAChRs), the detailed mechanisms of this activation remain to be addressed. METHODS: In the current study, we recorded GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) from dissociated SNc dopaminergic neurons that were obtained using an enzyme-free procedure. These neurons preserved some functional terminals after isolation, including those that release GABA. RESULTS: We found that both extra- and intra-cellular calcium modulates sIPSCs in these neurons. Furthermore, both nicotine and endogenous acetylcholine enhance the frequency of sIPSCs. Moreover, endogenous acetylcholine tonically facilitates sIPSC frequency, primarily by activating the alpha4beta2* nAChRs on the GABAergic terminals. CONCLUSION: Nicotine facilitates GABA release onto SNc dopaminergic neurons mainly via the activation of presynaptic alpha4beta2* nAChRs.

Iptakalim modulates ATP-sensitive K(+) channels in dopamine neurons from rat substantia nigra pars compacta.

Iptakalim, a novel cardiovascular ATP-sensitive K(+) (K(ATP)) channel opener, exerts neuroprotective effects on dopaminergic (DA) neurons against metabolic stress-induced neurotoxicity, but the mechanisms are largely unknown. Here, we examined the effects of iptakalim on functional K(ATP) channels in the plasma membrane (pm) and mitochondrial membrane using patch-clamp and fluorescence-imaging techniques. In identified DA neurons acutely dissociated from rat substantia nigra pars compacta (SNc), both the mitochondrial metabolic inhibitor rotenone and the sulfonylurea receptor subtype (SUR) 1-selective K(ATP) channel opener (KCO) diazoxide induced neuronal hyperpolarization and abolished action potential firing, but the SUR2B-selective KCO cromakalim exerted little effect, suggesting that functional K(ATP) channels in rat SNc DA neurons are mainly composed of SUR1. Immunocytochemical staining showed a SUR1-rather than a SUR2B-positive reaction in most dissociated DA neurons. At concentrations between 3 and 300 microM, iptakalim failed to hyperpolarize DA neurons; however, 300 microM iptakalim increased neuronal firing. In addition, iptakalim restored DA neuronal firing during rotenone-induced hyperpolarization and suppressed rotenone-induced outward current, suggesting that high concentrations of iptakalim close neuronal K(ATP) channels. Furthermore, in human embryonic kidney 293 cells, iptakalim (300-500 microM) closed diazoxide-induced Kir6.2/SUR1 K(ATP) channels, which were heterologously expressed. In rhodamine-123-preloaded DA neurons, iptakalim neither depolarized mitochondrial membrane nor prevented rotenone-induced mitochondrial depolarization. These data indicate that iptakalim is not a K(ATP) channel opener in rat SNc DA neurons; instead, iptakalim is a pm-K(ATP) channel closer at high concentrations. These effects of iptakalim stimulate further pharmacological investigation and the development of possible therapeutic applications.

[The study of the mechanisms underlying the effects of general anesthetics on spinal cord].

There are very extensive and complex effects of general anesthetics on spinal cord, so the advanced study on the mechanisms underlying the effects of general anesthetics at the spinal cord level will undoubtedly promote the more reasonable application of the general anesthetics and the understanding of mechanisms of general anesthesia. This paper reviews the actions of general anesthetics on neurons, synaptic transmissions, related receptors as well as ion channels in the spinal cord.