Differential downregulation of protein kinase C isoforms in spreading depression.
Spreading depression (SD) is a propagating depolarization of populations of neurons induced by intense electrical, chemical, or mechanical stimulation, which has been proposed to be an important mechanism in the aura of migraine. SD is characterized by a transient loss of synaptic transmission and thus may involve signal transduction mechanisms known to modulate synaptic strength. To examine the underlying pathophysiological molecular mechanisms of SD, we analyzed the regulation of eight protein kinase C (PKC) isoforms by immunoblot during SD induced by a high-intensity stimulus of synaptic afferents in the CA1 region of hippocampal slices. We observed a downregulation of the conventional (alpha, beta I, beta II, gamma) and the novel (delta, epsilon, eta) PKC isoforms in SD, but no change in the atypical isozyme (zeta). The coordinate downregulation of multiple PKC isoforms may be important in the functional depression of neuronal activity in SD. In contrast, the atypical zeta, and its constitutively active fragment PKM zeta, is a specific PKC isozyme that has been implicated in the maintenance of long-term potentiation (LTP) and long-term depression (LTD), widely studied models for the mechanism of memory. The stability of PKC zeta and PKM zeta in SD indicates that a molecular mechanism for the maintenance of LTP/ LTD is relatively resistant to alterations that occur during pathophysiologically large ionic fluxes. This result could help to explain the retention of information stored in the cortex despite the massive release of excitatory neurotransmitter and neuronal depolarization that may occur during the migrainous aura.
Osten
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P
Laboratory of Molecular Neuroscience, SUNY Health Science Center at Brooklyn 11203, USA.
Hrabetova
S
S
Sacktor
T C
TC
D000818:Animals; D015153:Blotting, Western; D013181:Cortical Spreading Depression / Q000502:physiology*; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000737:chemistry / Q000201:enzymology; D007527:Isoenzymes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D009924:Organ Culture Techniques; D011493:Protein Kinase C / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D011493:Protein Kinase C