Forskolin modulates acetylcholine receptor gating by interacting with the small extracellular loop between the M2 and M3 transmembrane domains

1. Forskolin acts as an allosteric modulator of muscle-type nicotinic acety lcholine receptors. Receptors from mouse muscle and Torpedo electroplax dem onstrate differential sensitivity to inhibition by forskolin. Previous work from this laboratory suggested that the gamma subunit is responsible for t his differential sensitivity. 2. We have used a series of mouse/Torpedo species-chimeric gamma subunits t o further define the site of forskolin interaction with the gamma subunit. Analysis of the patterns of forskolin inhibition of receptors containing mo use/Torpedo chimeric gamma subunits along with the mouse alpha, beta, and d elta subunits suggests that forskolin interacts with the small extracellula r domain that links the M2 and M3 transmembrane domains (the M2-M3 linker). 3. We suggest that the M2-M3 linker domain plays an important role in the t ransduction of ligand binding to the conformational changes that result in channel opening.