Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology

Abstract

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 (α2-α10) and three beta (β2, β3, and β4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although α4β2-and α7-nAChRs are the two major functional nAChR types in the CNS, α6*-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 α6*-nAChRs have been assessed with the use of α6 subunit blockers such as α-conotoxin MII and PIA, and also by using α6 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), α6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, α6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, α6*-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 α6*-nAChR function, pharmacology and pathophysiology.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

“…These channels can exist in either homomeric or heteromeric form, with the a7 subunit composing the most common homomeric nAChR in the CNS, and pentameric mixtures of a (a2-a10) and b (b2-b4) subunits, with a4b2*-nAChRs as the most common heteromeric CNS receptor (Taylor et al, 2013a). Although nAChRs are of a wide variety in the VTA (Wooltorton et al, 2003), heteromeric a6*-nAChRs are highly expressed in the mesolimbic DA system (Champtiaux et al, 2003;Yang et al, 2009bYang et al, , 2011 and a6 is the primary a subunit that plays a prominent role in DA release (Quik et al, 2011), and they are predominantly expressed in catecholaminergic systems (Brunzell, 2012). a6*-nAChR subunits are functional in recombinant systems when paired with b subunits or hybrids of a subunits.…”

Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

“…Single neurons were acutely dissociated from the VTA of 2-3-weekold mice (from Charles River), following procedures as previously described [33,34]. Briefly, mice were anesthetized with isoflurane, and brain tissue was rapidly removed and immersed in cold (2-4°C) artificial cerebrospinal fluid (ACSF), which contained (in mM): 124 NaCl, 5 KCl, 24 NaHCO 3 , 1.3 MgSO 4 , 1.2 KH 2 PO 4 , 2.4 CaCl 2 , and 10 glucose; pH 7.4.…”

“…Perforated-patch whole-cell recording techniques were employed [33,34]. Compared to performing conventional whole-cell recordings, this approach was crucial for obtaining stable nAChR responses from dissociated VTA neurons, presumably due to minimal perturbation of the intracellular environment.…”

“…Under these conditions, dissociated single neurons have no presynaptic terminals/ boutons [34]. Thus, this single neuron model has only postsynaptic receptors.…”

Effects of L-arginine and Nω-nitro-L-arginine methylester on learning and memory and α7 nAChR expression in the prefrontal cortex and hippocampus of rats

“…The α7 nAChR, one of the most widespread nAChR subtypes in the brain [15] , has been shown to be involved in improving cognitive function and spatial learning [16,17] .…”