Phorbol ester-mediated enhancement of hippocampal noradrenaline release: which ion channels are involved?
Enhancement of neurotransmitter release following phorbol ester-induced activation of protein kinase C (PKC) may be mediated by changes in ion conductance through the presynaptic membrane. This question was studied with rabbit hippocampal slices preincubated with [3H]noradrenaline ([3H]NA). NA release was evoked by pulses of either high K+ or Ca2+ (in the presence of high K+), or by electrical field stimulation. 4 beta-Phorbol 12,13-dibutyrate (PDB) increased and polymyxin B (PMB) reduced the K+-evoked NA release independent of the K+ concentration used for depolarization. The effects of PDB and PMB were not reduced by tetrodotoxin. PDB still enhanced the NA release triggered by short Ca2+ pulses in depolarized, axon terminal membranes (30 mM K+ and no Ca2+). The electrically evoked NA release was markedly enhanced by PDB even in the absence of Cl- in the medium or in the presence of the K+ channel blockers, tetraethylammonium, 4-amino- and 3,4-diaminopyridine. The inhibitory effect of the Ca2+ channel blocker, Cd2+, remained almost unchanged in the presence of PDB. It is concluded that PKC activation facilitates NA release in the hippocampus but not via presynaptic changes in Na+, K+ or Cl- currents. Whether phorbol ester mediates an increased intracellular Ca2+ availability, or whether a triggering 'normal' Ca2+ influx simply initiates, and synergistically supports, the PKC-mediated reactions leading to enhanced exocytosis, cannot be decided from the results of the present experiments.
Huang
H Y
HY
Institut für Pharmakologie und Toxikologie, Universität Freiburg, F.R.G.
Allgaier
C
C
Hertting
G
G
Jackisch
R
R
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004558:Electric Stimulation; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011817:Rabbits
D007473:Ion Channels; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine