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Co-expression of the neuronal alpha7 and L247T alpha7 mutant subunits yields hybrid nicotinic receptors with properties of both wild-type alpha7 and alpha7 mutant homomeric receptors



Co-expression of the neuronal alpha7 and L247T alpha7 mutant subunits yields hybrid nicotinic receptors with properties of both wild-type alpha7 and alpha7 mutant homomeric receptors



Proceedings of the National Academy of Sciences of the United States of America 94(4): 1539-1543



Injection of cDNA encoding the neuronal alpha-7 subunit into Xenopus oocytes yields homomeric receptors showing responses to AcCho that have low affinity, fast desensitization, nonlinear current-voltage (I-V) relation, and sensitivity to alpha-bungarotoxin (alpha-BTX) and 5-hydroxytryptamine (5HT), both substances acting as antagonists. Mutation of the Leu-247, located in the channel domain, changes 5HT from an antagonist to an agonist, slows the rate of desensitization, renders the I-V relation linear, and increases the affinity for acetylcholine (AcCho). A study was made of receptors expressed after injecting Xenopus oocytes with mixtures of cDNAs encoding the wild-type alpha-7 (WT alpha-7) and the L247T alpha-7 mutated nicotinic AcCho receptors (nAcChoRs). The receptors expressed were again blocked by alpha-bungarotoxin (100 nM) but exhibited both WT alpha-7 and alpha-7 mutant functional characteristics. Out of eight different types of hybrid receptors identified, most were inhibited by 5HT (1 mM) and showed low sensitivity to AcCho, like the WT alpha-7 receptors, but exhibited a slow rate of desensitization and an I-V relation similar to those of alpha-7 mutant receptors. Together, these findings indicate that the increased nAcChoR affinity and the decreased nAcChoR desensitization after Leu-247 mutation are uncoupled events. We propose that receptor diversity is predicted by permutations of WT alpha-7 and L247T alpha-7 subunits in a pentameric symmetrical model and that even partial replacement of Leu-247 with a polar residue within the leucine ring in the channel domain considerably influences the properties of neuronal alpha-7 nAcChoRs.

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Accession: 008337578

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PMID: 9037089


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