Nicotinic α5 subunit deletion locally reduces high‐affinity agonist activation without altering nicotinic receptor numbers

Brown, Rob; Collins, Allan C.; Lindstrom, Jon; Whiteaker, Paul

doi:10.1111/j.1471-4159.2007.04700.x

Cited by 77 publications

(85 citation statements)

References 38 publications

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“…In agreement with data obtained from studies using recombinant nAChRs, ex vivo studies have shown that brain nAChRs can contain more than two types of  subunit: for example, approximately 20% of α4β2* nAChRs also contain the 5 subunit, which is widespread in the brain [58]. Deletion of thesubunit reduces the high affinity agonist activation of presynaptic nAChRs in the striatum and thalamus without altering their number, and these results indicate that the primary effect of  incorporation is to increase nAChR function without affecting nAChR expression, which may explain why α5 Ko mice are less sensitive to the acute effects of nicotine administration [59,60].…”

Section: Native Nachr Subtypessupporting

confidence: 84%

Structural and functional diversity of native brain neuronal nicotinic receptors

Gotti

Clementi

Fornari

et al. 2009

Biochemical Pharmacology

415

430

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Although some of the neural circuits involved in the acute and chronic effects of nicotine have been identified, much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions.We briefly review some recent findings concerning the structure and function of native nAChRs, focusing on the subtypes identified in the meso-striatal and habenulo-interpeduncular pathways, two systems involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the effect of chronic nicotine on the expression of native subtypes.

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Section: Native Nachr Subtypessupporting

confidence: 84%

Structural and functional diversity of native brain neuronal nicotinic receptors

Gotti

Clementi

Fornari

et al. 2009

Biochemical Pharmacology

415

430

View full text Add to dashboard Cite

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“…For example, the ratio of ␣ 4 to ␤ 2 subunits has recently been shown to have profound effects on the activation and desensitization parameters of DH␤E-sensitive nicotinic receptors (Moroni et al, 2006;Tapia et al, 2007). Inclusion of the ␣ 5 accessory subunit is also thought to alter several parameters of ␣ 4 ␤ 2 * nicotinic receptors (Brown et al, 2007;Tapia et al, 2007;Kuryatov et al, 2008). Layer VI is one of a small number of brain regions that express the ␣ 5 nicotinic subunit (Wada et al, 1990;Marks et al, 1992;Salas et al, 2003), and our data suggest that these subunits are present in the receptors mediating the layer VI nicotinic currents over the age range examined (P10 -P41).…”

Section: Developmental Changes In Layer VI Nicotinic Receptorsmentioning

confidence: 50%

Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors

Kassam¹,

Herman²,

Goodfellow³

et al. 2008

J. Neurosci.

129

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In this study, we show robust nicotinic excitation of pyramidal neurons in layer VI of prefrontal cortex. This layer contains the corticothalamic neurons, which gate thalamic activity and play a critical role in attention. Our experiments tested nicotinic excitation across postnatal development, using whole-cell recordings in prefrontal brain slices from rats. These experiments showed that layer VI neurons have peak nicotinic currents during the first postnatal month, a time period of intensive cortical development in rodents. We demonstrate that these currents are mediated directly by postsynaptic nicotinic receptors and can be suppressed by a competitive antagonist of ␣ 4 ␤ 2 * nicotinic receptors. To record from identified corticothalamic neurons, we performed stereotaxic surgery to label the neurons projecting to medial dorsal thalamus. As hypothesized, recordings from these retrogradely labeled neurons in layer VI showed prominent nicotinic currents. Finally, we examined the effects of the drug nicotine on layer VI neurons and probed for the potential involvement of the accessory subunit, ␣ 5 , in their receptors. A level of nicotine similar to that found in the blood of smokers elicits a stable inward current in layer VI neurons, yet this exposure desensitizes ϳ50% of the subsequent current elicited by acetylcholine. An allosteric modulator of ␣ 4 ␤ 2 ␣ 5 receptors resulted in a 2.5-fold potentiation of submaximal nicotinic currents. This result is consistent with the expression of the relatively rare ␣ 5 nicotinic subunit in layer VI. In summary, we show that layer VI corticothalamic neurons can be strongly excited during development by an unusual subtype of nicotinic receptor.

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“…This finding argues that at least some of the nAChRs that modulate the αCtxMII-resistant component of dopamine release are α4α5β2 nAChRs. A similar functional decrease, with no decrease in receptor number, is seen in the α5 null mutant mouse when function is measured by 86 Rb + efflux [107]. Given that α5 gene deletion did not change cytisine-sensitive [ 3 H]-epibatidine binding (Figure 3), we suspect that both α4β2 and α4α5β2 nAChRs are normally expressed in striatal dopaminergic nerve terminals and that α4β2 nAChRs replace the α4α5β2 nAChRs in the α5 null mutant mice.…”

mentioning

confidence: 55%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

Self Cite

229

223

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This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

show abstract

Nicotinic α5 subunit deletion locally reduces high‐affinity agonist activation without altering nicotinic receptor numbers

Cited by 77 publications

References 38 publications

Structural and functional diversity of native brain neuronal nicotinic receptors

Structural and functional diversity of native brain neuronal nicotinic receptors

Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

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