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During the period covered by the report our groups were engaged in studying various aspects of the synaptic transmission. It has been shown that variouspresynaptic modulations increasing release of the neurotransmitters, e.g. activation of protein kinase C, inhibition of adenosine A1 receptors, blockade ofvoltage-operated potassium channels lead to significant potentiation of synaptic efficacy and unproportional increase of the contribution of NMDA receptorsinto the whole synaptic event. This selective potentiation of NMDA components of the EPSC can be of significant importance during some pathological states,since we discovered that short hypoxic- aglycaemic episode lead to the long-term preferential increase of the NMDA component. Our most recent dataindicate that the observed non-proportional enhancement of the NMDA component of the EPSC is due to the spill-over of glutamate beyond the synaptic cleftand subsequent activation of extrasynaptic glutamate, primarily NMDA receptors due to their affinity to the transmitter.
The neurotransmitter release is crucially dependent on the activity of Na+ and Ca2+ channels. In several studies supported by INTAS grant we elucidated the
action of some natural pepper components, kavain and methysticin, on the Na+ currents in isolated hippocampal cells. Obtained data allow to propose thesecompounds as possible drugs in treatment of neurological disorders. Modulation of Ca2+ channels by excitatory amino acids was also studied on isolatedhippocampal neurons. While glutamate blocked Ca2+ currents, it appeared that D-aspartate selectively potentiated some portions of Ca2+ current which wasnot associated with N-, P-, or Q-types of Ca2+ currents. Also, peculiarities of Ca2+ channel modulation were studied using point mutations and recombinantCa2+ channels. It was found that certain amino acid sequences from L-type Ca2+ channels transferred to other type channels are able to induce the sensitivityof these mutant channels to L-type Ca2+ channel blocker.
Apart from these excessive release of glutamate and other excitatory amino acids during many neurological disorders, significant elevations of extracellular K+concentrations are often observed. To reveal possible effects of such events we studied the action of elevated K+ on isolated hippocampal neurons. In themajority of Ca1-Ca3 cells the shift of external K+ form 0-2 mM to 2-20 mM was followed by a slow development of the current which had inward directionwhen measured at negative holding voltages from -120 to -40 mV. The amplitude of this current (but not its kinetics) was determined by the K+ concentration.We suggest that the development of this current is due to the substitution of Na+ by K+ ions at the site(s) responsible for the channel's permeability. The K+activated current may serve as a sensor of external K+ concentrations, and thus could be one important mechanism reducing excessive depolarization andmembrane excitability during ischaemia.
The techniques developed in Liverpool have allowed imaging of Ca2+ movement through intracellular organelles and very recently high resolution imaging ofexocytic events. The availability of many new fluorescent probes has helped this work along.
The most recent development is the direct measurement of calmodulin movement inside individual cells in response to evoked intracellular Ca2+ signals. Theconfocal measurement of fluorescence from labeled calmodulins show that Ca2+ induces a major translocation into the nucleus. In fact the nucleus acts anintegrator of pulses of calmodulin movements into the nuceoplasm. This has considerable consequences for long-termed potentiation.
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