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Journal of Neuroscience, Vol 6, 475-480, Copyright © 1986 by Society for Neuroscience
Phorbol esters mimic some cholinergic actions in hippocampal pyramidal neurons
RC Malenka, DV Madison, R Andrade and RA Nicoll
Muscarinic receptor stimulation in the hippocampus has been associated with
inositol phospholipid breakdown. In other systems this leads to the
formation of inositol trisphosphate and diacylglycerol, which promotes the
activation of protein kinase C. Phorbol esters, which directly activate
protein kinase C, exhibit high and specific binding in the hippocampus.
This, along with the advantages of the hippocampal slice preparation,
including direct pharmacological access to a cell population (CA1 pyramidal
cells) having clearly defined muscarinic responses, makes this an ideal
preparation to examine whether protein kinase C serves as the intracellular
signal for muscarinic receptor occupation. Like muscarinic agonists,
phorbol esters abolish the slow calcium-activated potassium
afterhyperpolarizing potential (AHP) and its underlying current without
reducing calcium action potentials. Those phorbol analogs that do not
activate kinase C have no effect, suggesting that activation of this enzyme
is required to reduce the AHP. The accommodation of spike discharge
normally seen during a long depolarizing stimulus is also markedly reduced
by phorbol esters as well as by muscarinic receptor activation. However,
unlike muscarinic agonists, phorbol esters have no effect on the
muscarine-sensitive, voltage-dependent, potassium current termed IM, nor do
they consistently cause an increase in input resistance. Moreover, unlike
ACh, they do not appear to have a presynaptic inhibitory action on the fast
EPSP elicited by orthodromic stimulation. The slow cholinergic EPSP was
blocked by phorbol esters, but this could be accounted for by a
postsynaptic action. Thus, if inositol phospholipid turnover is involved in
mediating muscarinic responses in the hippocampus, the activation of
protein kinase C can account for only part of the electrophysiological
response.
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