Nicotine mechanisms in Alzheimer’s diseaseOverview of nicotinic receptors and their roles in the central nervous system
Introduction
Nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of ligand-gated ion channels that includes γ-aminobutyric acid A (GABAA), glycine, and serotonin 3 (5-HT3) receptors Albuquerque et al 1997, Dani 2000, Dani et al 2000, Dani and Heinemann 1996, Dani and Mayer 1995, Jones et al 1999, Lena and Changeux 1998, Lindstrom 1997, Lindstrom et al 1996, Luetje et al 1990, McGehee and Role 1995, Role and Berg 1996, Sargent 1993, Wonnacott 1997. Agonists, such as endogenous acetylcholine or exogenous nicotine, stabilize the open conformation of the nAChR channel, which transiently permeates cations before closing back to a resting state or to a desensitized state that is unresponsive to agonists.
Section snippets
Multiple subunits produce nicotinic receptor diversity
The structure of the nicotinic receptor–channel complex arises from five polypeptide subunits assembled like staves of a barrel around a central water-filled pore (Cooper et al 1991). Although various subunit combinations can produce many different nAChR subtypes, the nicotinic receptor/channel family can be separated into three general functional classes that are consistent with their evolutionary development and their pharmacologic and physiologic properties: muscle subunits (α1, β1, δ, ϵ,
Expression of nAChRs in the CNS
Most nAChRs in the mammalian brain contain either α4β2 or α7 Charpantier et al 1998, Cimino et al 1992, Clarke et al 1985, Schoepfer et al 1990, Seguela et al 1993, Wada et al 1989, Wada et al 1990. Although many of the nAChRs contain α4 and β2 subunits, agonist and antagonist profiles differ for cells derived from different nuclei. For example, both medial habenula and locus coeruleus neurons express functional nAChRs with a pharmacologic profile that is consistent with α3 and β4 subunits in
Basic functions of nicotinic receptors
Upon binding ACh, the nAChR ion channel is stabilized in the open conformation for several milliseconds. Then the open pore of the receptor/channel closes to a resting state or closes to a desensitized state that is unresponsive to ACh or other agonists for many milliseconds or more. While open, nAChRs conduct cations, which can cause a local depolarization of the membrane and produce an intracellular ionic signal.
Although sodium and potassium carry most of the nAChR current, calcium can also
Competing processes of nAChR activation and desensitization
At a cholinergic synapse, approximately 1 mmol/L ACh is rapidly released into the cleft, immediately activating the nicotinic receptors. In a few milliseconds, the ACh is hydrolyzed by acetylcholinesterase and/or diffuses away. The delivery and removal of ACh is very rapid, and therefore desensitization is usually not thought to be important even though the desensitization process is complex. As neuronal nicotinic receptors are diverse and neuronal synapses are anatomically and compositionally
Main cholinergic projections
Before looking further into the roles of nAChRs, we need to consider some of the basic properties of the cholinergic innervation. Cholinergic systems provide diffuse innervation to practically all of the brain, but a relatively small number of cholinergic neurons innervate each neural area Kasa 1986, Woolf 1991. Despite the sparse innervation, cholinergic activity drives or modulates a wide variety of behaviors. By initially acting on nAChRs, nicotine or nicotinic innervation can increase
Nicotinic mechanisms in the CNS
The most widely observed synaptic role of nAChRs in the CNS is to influence neurotransmitter release. Figure 2 depicts presynaptic nAChRs, which have been found to increase the release of nearly every neurotransmitter that has been examined Albuquerque et al 1997, Alkondon et al 1997a, Gray et al 1996, Guo et al 1998, Jones et al 1999, Li et al 1998, McGehee et al 1995, McGehee and Role 1995, Radcliffe and Dani 1998, Radcliffe et al 1999, Role and Berg 1996, Wonnacott 1997. Exogenous
Acknowledgements
Work from this laboratory is supported by National Institutes of Health grants from the National Institute on Drug Abuse (Nos. DA09411 and DA12661) and from the National Institute of Neurological Disorders and Stroke (No. NS21229).
Aspects of the work were presented at the symposium “Nicotine Mechanisms in Alzheimer’s Disease,” March 16–18, 2000, Fajarko, Puerto Rico. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by
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