REGULATION OF PERIPHERAL AUTONOMIC FUNCTION AND NEUROENDOCRINE RESPONSES

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This year began with a focus on the role of ATP sensitive potassium channels (KATP) in modulating neurotransmission involved in movement disorders. KATPs are heteromultimers of a channel forming protein (Kir6.2) and a sulfonylurea receptor protein (SUR). They are found in a variety excitable cells, including neurons of the central nervous particularly in brain regions associated with the control of movement, i.e. motor and cerebellar cortex, globus pallidus (GP), and substantia nigra (SN). Studies were designed to diminish KATP by intracerebral administration of antisense oligodeoxyribonucleotides (ODNs) designed to hybridize to the AUG translation initiation codon of the mRNA encoding Kir6.2. We reduced expression of Kir6.2 mRNA by administration of Kir6.2 antisense ODN into the GP and found that this was attended by a decrease in apomorphine-induced contralateral turning in 6-OHDA hemiparkinsonian rats. In view of the association between KATP and the GABAergic system and the pivotal role of GABA in regulating motor activity, it appears likely that enhanced GABA release in the basal ganglia explains this altered behavioral response to apomorphine. In related studies, the effects of sulfonylureas on dopamine metabolism in PC12 cells in culture were examined. These drugs, as well as probenecid, were found to interfere with outward transport of DOPAC and HVA from PC12 cells. The anion transporter is ATP-dependent, unidirectional, and reversibly inhibited by sulfonylureas. Diazoxide, which is considered to be a KATP channel opener, also blocks this transporter. The transporter is different from the MDR transporter because the latter is not blocked by diazoxide, although it is blocked by sulfonylureas; in fact, some sulfonylureas have proven to be more effective than indomethacin, the standard for blocking MDR transporters. We are currently characterizing this apparently novel transporter. Over expression of SUR/Kir6.2 results in the appearance of KATP in PC12 cells and appears to have a neuroprotective effect from oxidative stress. Oxidative deamination of dopamine results in the formation of 3,4-dihydroxyphenylacetaldehyde (DOPAL). This compound is normally converted to 3,4-dihydroxyphenylacetic acid (DOPAC) via NAD-dependent aldehyde dehydrogenase. Under conditions in which this enzyme does not function adequately, because of inhibition by a drug (e.g., antabuse), by acetaldehyde, or by relative lack of NAD, 3,4-dihydroxyphenylethanol (DOPET) is formed. In our studies with PC12 cells, we have found that rotenone and MPP+, which inhibit Complex I of the mitochondrial electron transport system (and the conversion of NADH to NAD) there is a marked increase in DOPET formation and a decrease in DOPAC levels. Formation of DOPET is inhibited by drugs that block NADPH- dependent aldehyde/aldose reductases. Thus, DOPET formation may provide a convenient means of assessing mitochondrial complex I dysfunction (which has been implicated in the pathogenesis of Parkinson's disease). Since dopaminse is formed and metabolized to DOPAC in noradrenergic as well as dopaminergic neurons, DOPET formation may be usefully applied to assess complex I integrity in all catecholaminergic neurons. These results will contribute to our understanding of the role of KATP in regulation neurotransmitter function in movement disorders, may provide insights into the mechanism(s) responsible for initiation of programmed cell death in parkinsonian syndromes and other disorders affecting catecholaminergic neurons, and have direct clinical application in providing a means for assessing the presence of complex I mitochondrial defects or hypoxic conditions that interfere with mitocondrial electron transport in catecholaminergic neurons.