Up-regulation of human α7 nicotinic receptors by chronic treatment with activator and antagonist ligands

Molinari, Eduardo J.; Delbono, Osvaldo; Messi, Marı́a Laura; Renganathan, Muthukrishnan; Arnerić, Stephen P.; Sullivan, James P.; Gopalakrishnan, Murali

doi:10.1016/s0014-2999(98)00084-3

Cited by 75 publications

(60 citation statements)

References 27 publications

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“…180,181 Upregulation of human a7-subunits was shown in human embryonic kidney (HEK) cells after chronic exposure to nicotine and other receptor ligands. 182 Data on a6* receptors upregulation is less clear. On the one hand, some in vivo reports support upregulation of a6-containing receptors in rats during long-term self-administration of nicotine.…”

Section: General Overviewmentioning

confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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Section: General Overviewmentioning

confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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“…Recovery from desensitization is very fast ( Ϸ 10 s) for fast-desensitizing native ␣BTX-sensitive receptors (Dani et al, 2000) even following prolonged exposure to nicotine (Kawai and Berg, 2001). For some ␣7 receptors, especially when heterologously expressed, recovery may be more complex and/or species dependent (Olale et al, 1997;Molinari et al, 1998).…”

Section: Homomeric ␣-Receptorsmentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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“…Physiologically relevant nicotine concentrations have been shown to upregulate ␣4␤2-containing receptors (e.g., Flores et al, 1991;Buisson and Bertrand, 2001). Upregulation of other receptor subtypes can occur with higher nicotine concentrations in some cells (e.g., Schwartz and Kenneth, 1985;Rogers and Wonnacott, 1997;Molinari et al, 1998). Nicotinic receptor upregulation has previously been reported to involve an increase in the number of receptors, but this is not associated with changes in mRNA and is thought to reflect increased assembly (Olale et al, 1997;Wang et al, 1998).…”

Section: Nicotinic Receptor Upregulationmentioning

confidence: 99%

Cellular and synaptic mechanisms of nicotine addiction

2002

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ABSTRACT:The tragic health effects of nicotine addiction highlight the importance of investigating the cellular mechanisms of this complex behavioral phenomenon. The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkaloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CNS, including the mesoaccumbens DA system, which ultimately leads to behavioral reinforcement and addiction. Recent findings from a number of laboratories have provided new insights into the biologic processes that contribute to nicotine self-administration.Examination of the nAChR subtypes expressed within the reward centers has identified potential roles for these receptors in normal physiology, as well as the effects of nicotine exposure. The high nicotine sensitivity of some nAChR subtypes leads to rapid activation followed in many cases by rapid desensitization. Assessing the relative importance of these molecular phenomena in the behavioral effects of nicotine presents an exciting challenge for future research efforts.

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Up-regulation of human α7 nicotinic receptors by chronic treatment with activator and antagonist ligands

Cited by 75 publications

References 27 publications

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Desensitization of neuronal nicotinic receptors

Cellular and synaptic mechanisms of nicotine addiction

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