Not just any free fatty acid inhibits the nicotinic acetylcholine receptor

PERILLO, V.L.; VALLÉS, A.S.; BARRANTES, F.J.; ANTOLLINI, S.S.

Potrero de los Funes, San Luis

Congreso; XLVII Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2011

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

To elucidate the mechanism involved in the non-competitive inhibition of the nicotinic acetylcholine receptor (AChR) caused by free fatty acids (FFAs), we studied the effect of FFAs with a single double-bond at different positions (ω6, ω9, ω11 and ω13, cis-18:1) on different AChR properties. Two FFAs (ω6 and ω9) reduced the duration of the channel open-state. The briefest component of the closed-time distribution remained unaltered, suggesting that ω6 and ω9 do not behave as typical open-channel blockers but rather as allosteric blockers. Fluorescence resonance energy transfer studies showed that all FFAs locate at the lipid-AChR interface, ω6 being restricted to annular sites and all others occupying non-annular sites. Fluorescence quenching studies of pyrene-labeled AChR indicate that all cis-FFAs produce AChR conformational changes at the transmembrane level. Using the AChR conformational-sensitive probe crystal violet, we observed that all unsaturated FFAs increase its KD in the AChR desensitized state, but only ω9, ω11 and ω13 cis-18:1 decrease its KD in the resting state. In conclusion, some FFAs appear to directly inhibit AChR function probably by localizing at superficial sites inside the membrane, whereas other FFAs modulate the receptor´s conformational states by a different mechanism.