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      Conotoxins Targeting Nicotinic Acetylcholine Receptors: An Overview

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          Abstract

          Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide variety of ion channels such as voltage-gated sodium- (Na V), potassium- (K V), and calcium- (Ca V) channels as well as nicotinic acetylcholine receptors (nAChRs) which are classified as ligand-gated ion channels. The mode of action of several conotoxins has been the subject of investigation, while for many others this remains unknown. This review aims to give an overview of the knowledge we have today on the molecular pharmacology of conotoxins specifically interacting with nAChRs along with the structure–function relationship data.

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          Mammalian nicotinic acetylcholine receptors: from structure to function.

          Edson Albuquerque, Edna Pereira, Manickavasagom Alkondon … (2009)
          The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.
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            Brain nicotinic acetylcholine receptors: native subtypes and their relevance.

            Cecilia Gotti, Michele Zoli, Francesco Clementi (2006)
            Neuronal nicotinic acetylcholine receptors comprise a heterogeneous class of cationic channels that is present throughout the nervous system. These channels are involved both in physiological functions (including cognition, reward, motor activity and analgesia) and in pathological conditions such as Alzheimer's disease, Parkinson's disease, some forms of epilepsy, depression, autism and schizophrenia. They are also the targets of tobacco-smoking effects and addiction. Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain. The lack of subtype-specific ligands and the fact that many neuronal cells express multiple subtypes initially hampered the identification of the different native nicotinic acetylcholine receptor subtypes, but the increasing knowledge of subtype composition and roles will be of considerable interest for the development of new and clinically useful nicotinic acetylcholine receptor ligands.
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              Habenular α5* nicotinic receptor signaling controls nicotine intake

              Christie D. Fowler, Qun Lu, Paul Johnson … (2011)
              Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco addiction and lung cancer, but underlying mechanisms are unknown. Here, we report dramatically increased nicotine consumption in mice with null mutation in Chrna5. This effect was `rescued' in knockout mice by re-expressing α5 subunits in medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice and disruption of IPN signaling increased nicotine intake in rats. Our findings suggest that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake.
              Article 0 comments Cited 182 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mar Drugs
                Journal ID (iso-abbrev): Mar Drugs
                Journal ID (publisher-id): marinedrugs
                Title: Marine Drugs
                Publisher: MDPI
                ISSN (Electronic): 1660-3397
                Publication date (Electronic): 22 May 2014
                Publication date Collection: May 2014
                Volume: 12
                Issue: 5
                Pages: 2970-3004
                Affiliations
                Toxicology and Pharmacology, KU Leuven (University of Leuven), O&N2 P.O.Box 922, Herestraat 49, 3000 Leuven, Belgium; E-Mails: eline.lebbe@ 123456pharm.kuleuven.be (E.K.M.L.); steve.peigneur@ 123456pharm.kuleuven.be (S.P.); wijesekaraliyanageisuru.wijesekara@ 123456pharm.kuleuven.be (I.W.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: jan.tytgat@ 123456pharm.kuleuven.be ; Tel.: +32-16-323404; Fax: +32-16-323405.
                Article
                Publisher ID: marinedrugs-12-02970
                DOI: 10.3390/md12052970
                PMC ID: 4052327
                PubMed ID: 24857959
                SO-VID: 66a9a388-3b30-4950-befc-11a7cca41373
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 31 March 2014
                Date revision received : 24 April 2014
                Date accepted : 28 April 2014
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: nicotinic acetylcholine receptor,cone snail toxins,α-conotoxins,mode of action,working mechanism,acetylcholine binding protein,crystallography,docking model
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: nicotinic acetylcholine receptor, cone snail toxins, α-conotoxins, mode of action, working mechanism, acetylcholine binding protein, crystallography, docking model

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