Novel interplay between agonist and calcium binding sites modulates drug potentiation of α7 acetylcholine receptor

MUKHTASIMOVA, N.; BOUZAT C * (ULTIMA AUTORIA COMPARTIDA); SINE S.

CELLULAR AND MOLECULAR LIFE SCIENCES

Springer Nature Switzerland AG

Lugar: BASEL; Año: 2024 vol. 81

1420-682X

Drug modulation of the α7 acetylcholine receptor has emerged as a therapeutic strategy for neurological, neurodegenerative,and inflammatory disorders. α7 is a homo-pentamer containing topographically distinct sites for agonists, calcium, and drugmodulators with each type of site present in five copies. However, functional relationships between agonist, calcium, anddrugmodulator sites remain poorly understood. To investigate these relationships, we manipulated the number of agonist bindingsites, and monitored potentiation of ACh-elicited single-channel currents through α7 receptors by PNU-120596 (PNU)both in the presence and absence of calcium. When ACh is present alone, it elicits brief, sub-millisecond channel openings,however when ACh is present with PNU it elicits long clusters of potentiated openings. In receptors harboring five agonistbinding sites, PNU potentiates regardless of the presence or absence of calcium, whereas in receptors harboring one agonistbinding site, PNU potentiates in the presence but not the absence of calcium. By varying the numbers of agonist and calciumbinding sites we show that PNU potentiation of α7 depends on a balance between agonist occupancy of the orthosteric sitesand calcium occupancy of the allosteric sites. The findings suggest that in the local cellular environment, fluctuations in theconcentrations of neurotransmitter and calcium alter this balance and modulate the ability of PNU to potentiate α7.