Mechanisms of Inhibition and Potentiation of α4β2 Nicotinic Acetylcholine Receptors by Members of the Ly6 Protein Family

Abstract

Background: Several Ly6 proteins inhibit ␣4␤2 nAChRs, but the underlying mechanisms and the properties of homologous modulatory proteins are not well understood. Results: Lynx2 reduces cell-surface levels of receptors, whereas Ly6g6e slows receptor desensitization. Conclusion: Ly6 proteins inhibit or potentiate ␣4␤2 function by distinct mechanisms. Significance: Ly6 proteins greatly expand the range of properties of ␣4␤2 nAChRs.

Isoform‐specific mechanisms of a3b4*‐nicotinic acetylcholine receptor modulation by the prototoxin lynx1

“…Recent investigations into the functional modulation of α4β2‐containing nAChR by endogenous prototoxin neuromodulators have converged on 2 distinct mechanisms. By forming stable complexes with nAChR subunits, prototoxins (represented by lynx1 and lynx2) have been shown to alter nAChR trafficking and insertion into the plasma membrane (15, 20), and prototoxins have also been shown to extend their role by inter‐acting directly with nAChR at the level of the plasma membrane. This is exemplified by the ability of ly6g6e to potentiate α4β2‐nAChR macroscopic function via slowed desensitization of α4β2‐nAChR currents (20).…”

“…By forming stable complexes with nAChR subunits, prototoxins (represented by lynx1 and lynx2) have been shown to alter nAChR trafficking and insertion into the plasma membrane (15, 20), and prototoxins have also been shown to extend their role by inter‐acting directly with nAChR at the level of the plasma membrane. This is exemplified by the ability of ly6g6e to potentiate α4β2‐nAChR macroscopic function via slowed desensitization of α4β2‐nAChR currents (20). In this study, we show for the first time that α3β4*‐nAChRs are subject to both mechanisms of regulation by lynx1, with the balance between mechanisms dictated by the particular α3β4*‐nAChR isoform being targeted.…”

“…Third, we have shown other examples of preferential prototoxin effects on nAChR isoforms that contain α(−)/(+)α interfaces [lynx1 at (α4β2) 2 α4‐nAChR and LYPD6B at (α3β4) 2 α3‐ and (α3β4) 2 α5‐nAChR] (15, 22). Finally, and more universally, as α(−) residues do not participate in canonical binding sites, preferential binding of prototoxin molecules to α(−)‐containing interfaces would explain the repeated observation of allosteric prototoxin effects at heteromeric nAChR subtypes (2, 20, 22).…”

“…Recent evidence has demonstrated the ability of several members of the prototoxin family to bind with and differentially modulate α4β2‐nAChR function (20) but, again, the subtype selectivity of these interactions is not known. However, other prototoxins are known to show decided preferences for their nAChR partners.…”

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…Lynx1 and Lynx2 were originally identified as proteins that modulated a range of nAChR channel properties, (especially α4β2*nAChRs) and were proposed to essentially serve as a brake on cholinergic signaling in the CNS. Additional family members have now been shown to interact with α4β2, as well as α7*nAChRs and to affect both channel functions and intracellular trafficking (Miwa et al, 2012; Nichols et al, 2014; Puddifoot et al, 2015; Wu et al, 2015). …”