Manganese is a neurotoxin causing manganism, a Parkinson-like clinical disorder. Manganese has been shown to interfere with dopaminergic neurotransmission, but the neurotoxic mechanism involved is not fully resolved. In the bivalve mollusc Crassostrea virginica also known as the eastern oyster, beating rates of lateral cilia of the gill are controlled by dopaminergic-serotonergic innervation originating from their cerebral and visceral ganglia. Terminal release of dopamine activates D2-like receptors on these gill cells inhibiting adenylyl cyclase and slowing cilia beating rates. In C. virginica, manganese treatment disrupts this dopaminergic innervation of the gill, preventing the normal cilio-inhibitory response of lateral cells to dopamine. In this study an adenylyl cyclase activator (forskolin) and two different inhibitors (MDL-12,330A and SQ 22,536) were used to determine if manganese had any effects on the adenylyl cyclase step of the dopamine D2 receptor signal transduction pathway. The results showed that neither the adenylyl cyclase activator nor the inhibitors were affected by manganese in the control of lateral ciliary activity. This suggests that in C. virginica the mechanism of manganese toxicity on the dopaminergic control of lateral ciliary activity is targeting an early step in the D2R signal transduction pathway, which may involve interference with D2 receptor activation or alternatively some other downstream signaling activity that does not affect adenylyl cyclase.
Lateral gill cilia of Crassostrea virginica are controlled by a serotonin‐dopamine (DA) innervation. DA is an inhibitory transmitter at gill causing cilio‐inhibition. Manganese (Mn) is a neurotoxin causing Manganism in people exposed to high levels in air. Clinical interventions for Manganism have not been successful. Recently, p‐aminosalicylic acid (PAS) was reported to provide effective treatment of Manganism. PAS is an anti‐inflammatory drug with chelating properties. We showed treatments of C. virginica with Mn disrupts DA innervation of gill. Pre‐or co‐treatments with PAS or EDTA prevented it. We hypothesized chelating agents would be effective in reversing neurotoxic effects of Mn when applied after Mn. We used gills of C. virginica to measure lateral cilia beating rates of preparations treated first with Mn followed by treatments with either PAS, EDTA or DMSA (meso‐2,3‐dimercaptosuccinic acid). Dose responses of PAS, EDTA and DMSA (10−11–10−4M) against beating were conducted after 100 FM of Mn was added to gill. All 3 drugs reversed the neurotoxic effects of Mn in a dose‐dependent manner. DMSA was the most potent. The study demonstrates these chelators are effective in reversing acute neurtoxicity of Mn. This information should be of interest to those designing therapeutic drug treatments for Manganism. Supported by 2R25GM06003 of NIGMS, 0516041171 of NYSDOE and 0622197 of NSF.
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.
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