Adenylyl Cyclase Inhibitors Reverse the Neurotoxic Effects of Manganese on Post‐Synaptic Dopamine D2 Receptors

Abstract

Manganese (Mn) is a neurotoxin causing Manganism. It disrupts dopamine (DA) systems. The mechanism is not fully resolved. Gill lateral cilia of Crassostrea virginica are innervated by DA cilio‐inhibitory nerves. Previously we showed post‐synaptic DA receptors in gill lateral cells are D2 metabotrophic type, G protein‐coupled (Gai/o). Gai inhibits adenylyl cyclase (AC). Gâã opens K+ and closes Ca2+ channels. We showed Mn blocks DA post‐synaptic receptor. Here we observed membrane potentials of these cells of C. virginica with a fluorescent dye while measuring cilia beating rates. Applying HT to gill caused membrane depolarization and increased cilia beating rates. Applying DA after exciting cilia repolarized the membrane and decreased beating. Mn prevented the cilio‐inhibitory response and repolarization. Applying ATP or forskolin, an AC activator, to control or Mn treated gills increased beating without changing membrane potential. Applying MDL or SQ, AC inhibitors, to controls or Mn treated gills decreased beating without affecting membrane potential. The study shows correlation between membrane potential and cilia beating rates; that actions initiated by activation of D2 receptors can be differentiated to effects on AC and membrane potential; and neurotoxic effects of Mn can be overcome by AC inhibitors. This information is helpful to understand causes and treatments of Manganism.