Vol. 61, Issue 1, 127-135, January 2002

Potentiation of Human 42 Neuronal Nicotinic Acetylcholine Receptor by Estradiol

Logos Curtis, Bruno Buisson,¹ Sonia Bertrand, and Daniel Bertrand

Department of Physiology, Faculty of Medicine, Genève, Switzerland

The modulation of neurotransmitter receptors by various substances can reflect important physiological mechanisms involved in the regulation of neural function. Furthermore, such substances, in particular specific allosteric modulators, can reveal promising therapeutic targets for diseases of the nervous system. From this perspective, we investigated the effects of the steroid hormone estradiol on human neuronal nicotinic acetylcholine receptors expressed either in Xenopus laevis oocytes or human embryonic kidney cells. Acetylcholine-evoked currents were potentiated both by pre- and coapplications of estradiol in 42 and 44 receptors, but not in 32 or 34 receptors. The reversible potentiation of 4-containing receptors could be induced within seconds in X. laevis oocytes and at micromolar concentrations of estradiol. The potentiation was greatest for responses evoked by low concentrations of acetylcholine, resulting in an apparent increase of receptor affinity. At the single channel level, estradiol potentiation resulted from an increase in opening probability. Finally, the use of functional chimeric or truncated 4 subunits demonstrated that a site at the C-terminal tail of the 4 subunit is required for estradiol potentiation. These results suggest the presence of a specific site at the human nicotinic acetylcholine receptor 4 subunit through which estradiol can cause an allosteric potentiation of acetylcholine-evoked responses.