Co-expression of the neuronal α7 and L247T α7 mutant subunits yields hybrid nicotinic receptors with properties of both wild-type α7 and α7 mutant homomeric receptors

Injection of cDNA encoding the neuronal α₇ 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 α-bungarotoxin (α-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 α₇ (WT α₇) and the L247T α₇ mutated nicotinic AcCho receptors (nAcChoRs). The receptors expressed were again blocked by α-bungarotoxin (100 nM) but exhibited both WT α₇ and α₇ 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 α₇ receptors, but exhibited a slow rate of desensitization and an I- V relation similar to those of α₇ mutant receptors. Together, these findings indicate that the increased nAcChoR affinity and the decreased nAc- ChoR desensitization after Leu-247 mutation are uncoupled events. We propose that receptor diversity is predicted by permutations of WT α₇ and L247T α₇ 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 α₇ nAcChoRs.