Protein kinase C and transmitter release.
1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca2+ entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca2+ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.
Majewski
H
H
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia. harry.majewski@med.monash.edu.au
Kotsonis
P
P
Iannazzo
L
L
Murphy
T V
TV
Musgrave
I F
IF
D000818:Animals; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D018377:Neurotransmitter Agents; D011493:Protein Kinase C; D009638:Norepinephrine