Choline is a Selective Agonist of α7 Nicotinic Acetylcholine Receptors in the Rat Brain Neurons

Abstract

In the present study, we demonstrate that choline, a precursor of acetylcholine (ACh) and a product of acetylcholine hydrolysis by acetylcholinesterase (AChE), acts as an efficient and relatively selective agonist of alpha7-containing nicotinic acetylcholine receptors (nAChR) in neurons cultured from the rat hippocampus, olfactory bulb and thalamus as well as in PC12 cells. Choline was able to activate postsynaptic and presynaptic alpha7 nAChRs, with the latter action resulting in the release of other neurotransmitters. Although choline was approximately one order of magnitude less potent than ACh (EC50 of 1.6 mM for choline and 0.13 mM for ACh), it acted as a full agonist at alpha7 nAChRs. In contrast, choline did not activate alpha4beta2 agonist-bearing nAChRs on hippocampal neurons, and acted as a partial agonist at alpha3beta4-containing nAChRs on PC12 cells. The ethyl alcohol moiety of choline is required for the selective action on alpha7 nAChR. Exposure of cultured hippocampal neurons for 10 min to choline (10-100 microM) resulted in desensitization of the native alpha7 nAChRs. Moreover, chronic exposure (10 days) of the cultured hippocampal neurons to a desensitizing concentration of choline (approximately 30 microM) decreased their responsiveness to ACh. The selective action of choline on native alpha7 nAChRs suggests that this naturally occurring compound may act in vivo as an endogenous ligand for these receptors. Putative physiological actions of choline include retrograde messenger activity during the development of the mammalian central nervous system and during periods of elevated synaptic activity that leads to long-term potentiation.

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

“…This would be consistent with suggestions that cholinergic innervation in the CNS, such as that provided by the septal input to the hippocampus, may be diffuse, delivering ACh at a distance for "volume transmission" (McKinney et al, 1983;Frotscher and Leranth, 1985;Descarries et al, 1997;Descarries, 1998;Zoli et al, 1999; but see Turrini et al, 2001). Because ␣7-nAChRs can also respond to choline as an agonist (Papke et al, 1996;Alkondon et al, 1997b), hydrolysis of ACh by extracellular acetylcholinesterase need not prevent distally released agonist from affecting the receptors. A sort of "regional" activation achieved by agonist delivered in this manner could be consistent with a variety of candidate modulatory roles for the receptors.…”

Potentiation and inhibition of neuronal α4β4 nicotinic acetylcholine receptors by choline

“…During the last few years, choline has received much attention because it is a selective and full agonist of a-bungarotoxin-sensitive, a7 subunit-containing nicotinic Ž acetylcholine receptors Papke et al, 1989;Alkondon et . al., 1997;Frazier et al, 1998;Alkondon et al, 1999 .…”

“…The threshold concentration of choline to activate a7 subunit-containing nicotinic acetylcholine receptors is ; 200 mM and the EC value of choline to 50 activate these a7 subunit-containing receptors is ; 2 mM Ž . Alkondon et al, 1997;Alkondon et al, 1999 . The threshold for the presently found co-agonist effect of choline at receptors that do not contain a7 subunits was 20-fold lower.…”

Desensitization of neuronal nicotinic receptors

“…Alternatively, in the CNS, mismatches between cholinergic terminals and postsynaptic receptors may require ACh to act over a distance (Zoli, 2000), which could lead to desensitization of nAChRs under certain conditions; for example, when acetylcholinesterase is inhibited, endogenous activation of presynaptic nAChRs on dopaminergic terminals in striatum undergoes profound desensitization (Zhou et al, 2001)-a process that may occur during the treatment of Alzheimer's disease using cholinesterase inhibitors. Likewise, if the selective ␣7*-nAChR agonist, choline, is utilized as an "ambient" central transmitter, desensitization of these receptors would become an important feature of their physiology (Alkondon et al, 1997). Desensitization of nAChRs during chronic exposure to nicotine may not only lead to receptor up-regulation (Fenster et al, 1999b), but likely has a critical role in promoting other forms of synaptic plasticity: in the hippocampus, nicotine facilitated long-term potentiation is mimicked by the selective antagonist MLA, implying that desensitization of ␣7 nAChRs contributes to this effect (Fujii et al, 2000).…”