A new look at the neuronal nicotinic acetylcholine receptor pharmacophore

Curtis, Logos; Chiodini, Florence; Spang, Jörg E; Bertrand, Sonia; Patt, J. T.; Westera, G.; Bertrand, Daniel

doi:10.1016/s0014-2999(00)00053-4

Cited by 20 publications

(14 citation statements)

References 29 publications

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“…In this layer, we found a strong reaction for the a5 and b2 chains that are known to alter the pharmacological properties of the ACh-R (Gerzanich et al, 1998;Curtis et al, 2000), whereas the a3 and b4 chains were less frequently detected. The cytoplasmic colocalization of different heterooligomers in a single cell layer of the stratum granulosum has not been observed before.…”

Section: Discussionmentioning

confidence: 82%

Phenotypical and Molecular Profiling of the Extraneuronal Cholinergic System of the Skin

Kurzen

Berger

Jäger

et al. 2004

Journal of Investigative Dermatology

122

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We present molecular and protein profiling of all acetylcholine receptors (ACh-R) in human scalp skin using PCR, in situ hybridization and double-labeling immunofluorescence. Within the epidermis, the nicotinic (n)ACh-R subunits, alpha3, alpha5, beta2, and beta4 were expressed in the basal cell layer (BCL) and in a single cell layer in the stratum granulosum; alpha9 was expressed in the basal and lower spinous layers. alpha7, alpha10, and beta1 were preferentially detected in the upper spinous and granular layers. Of the muscarinic (m)ACh-R, m1 and m4 were found in the suprabasal layers, whereas m2, m3, and m5 remained restricted to the lower layers. In the outer root sheath of the hair follicle, all ACh-R except alpha9, beta1, and m4 were found in the BCL whereas the alpha9, m4, and m5 ACh-R were restricted to the central cell layer. The alpha5, beta1, beta2, m1-m4 chains were strongly expressed in the inner root sheath. Undifferentiated sebocytes expressed the alpha3, alpha9, beta4, m3-m5 ACh-R whereas alpha7, beta2, beta4, m2, and m4 were found in mature sebocytes. In sweat glands, the alpha3*, alpha7, and m2-m5 ACh-R were most prominent in the myoepithelial cells whereas alpha9, beta2, m1, m3, and m4 ACh-R were present in the acinar cells. Taken together, our data result in a complete molecular map of the extraneuronal cholinergic system of the skin that may be translated into distinct functional reaction patterns.

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Section: Discussionmentioning

confidence: 82%

Phenotypical and Molecular Profiling of the Extraneuronal Cholinergic System of the Skin

Kurzen

Berger

Jäger

et al. 2004

Journal of Investigative Dermatology

122

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“…However, since in displacement affinity chromatography, binding affinities (K d values) are directly related to ml [31], and since with the nAChR there is a relationship between EC 50 and binding at the agonist binding site [8,9], comparative competitive displacement studies should be capable of the relative, qualitative determination of EC 50 values. As with the Cheng-Pursoff approach, the necessary requirements are that the agonists have an identical mechanism of action and that the experiments are performed under the same conditions.…”

Section: Resultsmentioning

confidence: 99%

“…The primary binding sites for agonists are located on the extracellular portion of the receptor in a pocket at the interface between the N-terminals of the ␣ and ␤ subunits [3,6,7]. One approach has been to construct pharmacophores of the agonist binding site [8,9] and to synthesize drug candidates which fit the conformational requirements of this site. This has led to the syntheses of conformationally constrained nicotine and anabasine analogues [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

On-line screening of conformationally constrained nicotines and anabasines for agonist activity at the α3β4- and α4β2-nicotinic acetylcholine receptors using immobilized receptor-based liquid chromatographic stationary phases

Moaddel

Jóźwiak

Yamaguchi

et al. 2004

Journal of Chromatography B

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“…Chimeric and mutant ␣3/␣4 subunits were generated using a PCR-based method described previously (Curtis et al, 2000). A3(202)␣4 and ␣4(202)␣3 cDNAs were constructed through two successive PCRs (conditions identical to Curtis et al, 2000) by using the following primers: ␣3-F (5Ј-AGCTTATGGCTCT-GGCCGTCTC-3Ј); ␣3(202)␣4-R (5Ј-CATAGGTGATGTCGGGGTA-GATCTCC-3Ј); ␣3(202)␣4-F (complementary to ␣3(202)␣4-R); ␣4-R (5Ј-CGCACTTCCTAGATCATGCCAGCC-3Ј); ␣4-F (5Ј-TCGATCTA-GAGCCCGCGAGGTG-3Ј); ␣4(202)␣3-R (5Ј-GTGATGTCGGGGTA-GATCTCG-3Ј); ␣4(202)␣3-F (complementary to ␣4(202)␣3-R); and ␣3-R (5Ј-GCAAGGCAGGCACACAGCTTAG). The ␣4(588)stop cDNA was constructed using one PCR (conditions identical to first PCR described in Curtis et al, 2000) and the following primers: ␣4-F and ␣4(588)stop-R (5Ј-CTACTAGGGCGGTAGGAAGAGGC-3Ј).…”

Section: Drugs and Solutionsmentioning

confidence: 99%

Potentiation of Human α4β2 Neuronal Nicotinic Acetylcholine Receptor by Estradiol

et al. 2002

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The modulation of neurotransmitter receptors by various substances can reflect important physiological mechanisms involved in the regulation of neural function. Furthermore, such substances, in particular specific allosteric modulators, can reveal promising therapeutic targets for diseases of the nervous system. From this perspective, we investigated the effects of the steroid hormone estradiol on human neuronal nicotinic acetylcholine receptors expressed either in Xenopus laevis oocytes or human embryonic kidney cells. Acetylcholine-evoked currents were potentiated both by pre-and coapplications of estradiol in ␣4␤2 and ␣4␤4 receptors, but not in ␣3␤2 or ␣3␤4 receptors. The reversible potentiation of ␣4-containing receptors could be induced within seconds in X. laevis oocytes and at micromolar concentrations of estradiol. The potentiation was greatest for responses evoked by low concentrations of acetylcholine, resulting in an apparent increase of receptor affinity. At the single channel level, estradiol potentiation resulted from an increase in opening probability. Finally, the use of functional chimeric or truncated ␣4 subunits demonstrated that a site at the C-terminal tail of the ␣4 subunit is required for estradiol potentiation. These results suggest the presence of a specific site at the human nicotinic acetylcholine receptor ␣4 subunit through which estradiol can cause an allosteric potentiation of acetylcholine-evoked responses.

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A new look at the neuronal nicotinic acetylcholine receptor pharmacophore

Cited by 20 publications

References 29 publications

Phenotypical and Molecular Profiling of the Extraneuronal Cholinergic System of the Skin

Phenotypical and Molecular Profiling of the Extraneuronal Cholinergic System of the Skin

On-line screening of conformationally constrained nicotines and anabasines for agonist activity at the α3β4- and α4β2-nicotinic acetylcholine receptors using immobilized receptor-based liquid chromatographic stationary phases

Potentiation of Human α4β2 Neuronal Nicotinic Acetylcholine Receptor by Estradiol

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