PubMed · 10728344
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M R Franz. 2000-01-14. Mechano-electrical feedback.. https://doi.org/10.1016/s0008-6363(99)00390-9
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The degradation of dopamine by monoamine oxidase (MAO) enzymes plays an important role in the function of dopamine receptors in the central nervous system. Accordingly, it has already been reported that the blockade of MAO by specific inhibitors prolongs the effects of dopamine on its receptors. By using intracellular electrophysiological recordings, here we report that the irreversible MAO A and B inhibitor tranylcypromine, but not the reversible MAO A inhibitor moclobemide, potentiates DA responses in rat midbrain dopaminergic neurones maintained in vitro. Moclobemide was not effective even when the MAO B enzymes were additionally blocked by the MAOI deprenyl. Thus, our electrophysiological findings confirm that the degradation DA is very important to control the effects of this catecholamine at a cellular level. Furthermore, they demonstrate that tranylcypromine potentiates DA neurotransmission while moclobemide is devoid of dopaminergic action in an in vitro condition. The phenomena reported above support the hypothesis that part of the antidepressant and antiparkinsonian effects of tranylcypromine depend on an action on DA transmission.
The role of Ca2+ entry in determining the electrical properties of cerebellar Purkinje cell (PC) dendrites and somata was investigated in cerebellar slice cultures. Immunohistofluorescence demonstrated the presence of at least three distinct types of Ca2+ channel proteins in PCs: the alpha1A subunit (P/Q type Ca2+ channel), the alpha1G subunit (T type) and the alpha1E subunit (R type). In PC dendrites, the response started in 66 % of cases with a slow depolarization (50 +/- 15 ms) triggering one or two fast (approximately 1 ms) action potentials (APs). The slow depolarization was identified as a low-threshold non-P/Q Ca2+ AP initiated, most probably, in the dendrites. In 16 % of cases, this response propagated to the soma to elicit an initial burst of fast APs. Somatic recordings revealed three modes of discharge. In mode 1, PCs display a single or a short burst of fast APs. In contrast, PCs fire repetitively in mode 2 and 3, with a sustained discharge of APs in mode 2, and bursts of APs in mode 3. Removal of external Ca2+ or bath applications of a membrane-permeable Ca2+ chelator abolished repetitive firing. Tetraethylammonium (TEA) prolonged dendritic and somatic fast APs by a depolarizing plateau sensitive to Cd2+ and to omega-conotoxin MVII C or omega-agatoxin TK. Therefore, the role of Ca2+ channels in determining somatic PC firing has been investigated. Cd2+ or P/Q type Ca2+ channel-specific toxins reduced the duration of the discharge and occasionallyinduced the appearance of oscillations in the membrane potential associated with bursts of APs. In summary, we demonstrate that Ca2+ entry through low-voltage gated Ca2+ channels, not yet identified, underlies a dendritic AP rarelyeliciting a somatic burst of APs whereas Ca2+ entry through P/Q type Ca2+ channels allowed a repetitive firing mainly by inducing a Ca2+-dependent hyperpolarization.
Using in situ hybridisation histochemistry in combination with patch-clamp recordings and specific pharmacological tools, the molecular nature of the channels underlying Ca2+-dependent K+ currents was determined in dorsal vagal neurones (DVNs) of rat brainstem slices. In situ hybridisation analysis at cellular resolution revealed the presence of 'big'-conductance Ca2+- and voltage-activated K+ (BK) channel alpha-subunit mRNA, and of only one 'small'-conductance Ca2+-activated K+ (SK) channel subunit transcript, SK3, at very high levels in DVNs. By contrast, SK1 and SK2 mRNAs were below the threshold limit of detection. The SK channel-mediated after-hyperpolarising current (IAHP) was blocked by apamin with a half-maximal inhibitory concentration of approximately 2.2 nM. This is consistent with homomultimeric SK3 channels mediating IAHP in DVNs. IAHP was also blocked by scyllatoxin (20-30 nM) and curare (100-200 microM). Application of apamin (100 nM) or scyllatoxin (20 nM) invariably caused a substantial increase to 146.1 +/- 10.4 and 181.8 +/- 12.9 % of control, respectively, in the spontaneous firing rate of DVNs. Action potential duration was not affected by these SK channel blockers. The selective BK channel blocker iberiotoxin (50 nM) increased action potential duration by 22.5 +/- 7.3 %, as did low concentrations of tetraethylammonium (0.5 mM; 99.3 +/- 16.4 %) and the Ca2+ channel blocker Cd2+ (100 microM; 49.5 +/- 20.9 %). BK channel blockade did not significantly affect the firing rate of DVNs. These results allow us to establish a tight correlation between the properties of cloned and native BK and SK channels, and to achieve an understanding, at the molecular level, of their role in regulating the spontaneous firing frequency and in shaping single action potentials of central neurones.