Nicotinic Receptor Function in the Mammalian Central Nervous System^a

Abstract

The diversity of neuronal nicotinic receptors (nAChRs) in addition to their possible involvement in such pathological conditions as Alzheimer's disease have directed our research towards the characterization of these receptors in various mammalian brain areas. Our studies have relied on electrophysiological, biochemical, and immunofluorescent techniques applied to cultured and acutely dissociated hippocampal neurons, and have been aimed at identifying the various subtypes of nAChRs expressed in the mammalian central nervous system (CNS), at defining the mechanisms by which CNS nAChR activity is modulated, and at determining the ion permeability of CNS nAChR channels. Our findings can be summarized as follows: (1) hippocampal neurons express at least three subtypes of CNS nAChRs--an alpha 7-subunit-bearing nAChR that subserves fast-inactivating, alpha-BGT-sensitive currents, which are referred to as type IA, and alpha 4 beta 2 nAChR that subserves slowly inactivating, dihydro-beta-erythroidine-sensitive currents, which are referred to as type II, and an alpha 3 beta 4 nAChR that subserves slowly inactivating, mecamylamine-sensitive currents, which are referred to as type III; (2) nicotinic agonists can activate a single type of nicotinic current in olfactory bulb neurons, that is, type IA currents; (3) alpha 7-subunit-bearing nAChR channels in the hippocampus have a brief lifetime, a high conductance, and a high Ca2+ permeability; (4) the peak amplitude of type IA currents tends to rundown with time, and this rundown can be prevented by the presence of ATP-regenerating compounds (particularly phosphocreatine) in the internal solution; (5) rectification of type IA currents is dependent on the presence of Mg2+ in the internal solution; and (6) there is an ACh-insensitive site on neuronal and nonneuronal nAChRs through which the receptor channel can be activated. These findings lay the groundwork for a better understanding of the physiological role of these receptors in synaptic transmission in the CNS.

Melatonin modulation of presynaptic nicotinic acetylcholine receptors located on short noradrenergic neurons of the rat vas deferens: a pharmacological characterization

“…Receptors composed of a7 subunits are known to present low affinity for [ 3 H]-(-)-nicotine in binding studies, but a high efficacy for (-)-nicotine in single channel conductance studies (15,16). On the other hand, these receptors exhibit low efficacy for DMPP and carbachol (17,18).…”

“…Mecamylamine (10 nM), a potent nAChR inhibitor composed of a3ß4 subunits (15,19), blocked with higher efficiency the nicotine-induced contraction of vasa deferentia isolated in the afternoon when compared to those isolated at night. On the other Figure 4 -Effect of endogenous and exogenous melatonin on mecamylamine (10 nM) inhibition of the noncumulative concentration-effect curve for nicotine in the prostatic portion of the rat vas deferens.…”

Rat neuronal nicotinic acetylcholine receptors containing α7 subunit: pharmacological properties of ligand binding and function

“…Since successful clonings of neuronal nAChR subunit genes (α2−α8, β2−β4) more than 20 years ago, many studies have demonstrated that functional nAChRs could be formed by heterologous expressions of α7 subunit alone [9-11, 35, 39] and that there are homomeric α7 nAChRs expressed in neuronal systems [40][41][42][43] . However, over the years, some experimental observations supported the notion that there may be heteromeric receptors containing α7 subunits in combination with other neuronal nAChR subunits [44][45][46][47] .…”

Unconventional ligands and modulators of nicotinic receptors

“…Considering that neuronal nAChRs have been found presynaptically controlling the release of numerous neurotransmitters and on postsynaptic neurons, such a chemical network will have a strong impact on establishing the overall degree of activity of a given circuitry in the brain (see Albuquerque et al, 1995).…”