Allosteric modulation of alpha7 nicotinic receptor by 5-hydroxyindol analyzed at the single-channel level

TOLOSA F.; BARTOS M; BOUZAT C

Bahía Blanca

Workshop; SAN Workshop Neuronal Communication: From structure to physiology?.; 2008

Sociedad Argentina de Investigación de Neurociencias (SAN)

Neuronal alpha7 nicotinic receptors show rapid activation and fast desensitization kinetics in the continued presence of agonist. This receptor has been shown to be involved in the regulation of interneuron excitability and modulation of release of neurotransmitters, and plays a neuroprotective role. Molecules that increase the response to agonists are known as positive allosteric modulators (PAMs). 5-Hydroxyindol (5-HI) has been shown to produce a significant increase of ACh-evoked macroscopic current in oocytes expressing alpha7. We here studied the effects at the single channel level of 5-HI on human alpha7 receptors expressed in BOSC cells. Single-channel activity of alpha7 receptors is detected at ACh concentrations higher than 10 µM. Activity appears as isolated brief openings with mean durations of 0.35 ± 0.1 ms. When ACh is co-applied with 2 mM 5-HI, single channels are detected at 5 µM ACh, indicating an increase in the potency for activation. Interestingly, the presence of the drug produces a 4-fold increase in the duration of the open channels. The same effect is observed for 5-HI concentrations between 100 µM and 2 mM. At lower concentrations (10 µM 5-HI) the mean duration increases only 2-fold. At 500 µM ACh, no changes in open channel lifetime is observed, indicating that modulation occurs only at suboptimal ACh concentrations. The use of positive allosteric modulators of alpha7 has recently emerged as a therapeutic strategy for disorders associated with receptor deficit, particularly those involving cognitive and attention deficits. Therefore, understanding their molecular mechanism is of significant importance.