A Role for the β₁-β₂Loop in the Gating of 5-HT₃Receptors

Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel

“…Based on the capability of the WT homomeric GluClα (GluClαWT) receptor to respond to Glu only following exposure to IVM, it was suggested that IVM binding induces a conformational change that enables coupling of Glu binding at α/α intersubunit interfaces to the opening of the ion-channel gate (14,23). To explore this suggestion further, we used a strategy of microchimerism that is based on previous studies showing that in various Cys-loop receptors, the β1β2, Cys, and β8β9 loops of the LigBD interact with the M2-M3 loop of the pore domain to couple neurotransmitter binding to channel gating (23,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) (e.g., Fig. 1 A and C).…”

“…In various Cys-loop receptors, the β1β2, Cys, and β8β9 loops were shown to play a key role in transducing the agonist-binding energy into ion-channel gating force (35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Here, we first demonstrated that although the homomeric GluClαR is not responsive to Glu, the β1β2, Cys, and β8β9 loops of the GluClα subunit are fully capable of coupling Glu binding to channel gating in a heteromeric GluClα/β microchimera that has the sequences of the α-subunit loops.…”

Using molecular dynamics to elucidate the structural basis for function in pLGICs

“…Unwin had noted this interaction and described it as a "pin in socket" interaction (4). Disulfide cross-linking studies have shown that these loops are in close proximity in both GABA A and 5-HT3 receptors (19,20). Interestingly, in the 5-HT3A receptor, mutation to Cys of the residue at the tip of the β1-β2 loop, K81, resulted in desensitization of the channels (20).…”

“…Disulfide cross-linking studies have shown that these loops are in close proximity in both GABA A and 5-HT3 receptors (19,20). Interestingly, in the 5-HT3A receptor, mutation to Cys of the residue at the tip of the β1-β2 loop, K81, resulted in desensitization of the channels (20). Covalent modification of the Cys with small sulfhydryl reagents partially restored channel function, whereas modification with larger sulfhydryl reagents completely restored function.…”

“…Covalent modification of the Cys with small sulfhydryl reagents partially restored channel function, whereas modification with larger sulfhydryl reagents completely restored function. It suggested that the interaction between the β1-β2 loop tip and the M2-M3 loop was important for recovery from fast desensitization (20). In the MD simulation, following ivermectin removal, the residue at the β1-β2 loop tip, V45, lifts upward to allow an absolutely conserved M2-M3 loop proline, P268, to move inward toward the central channel axis (2).…”