Protein kinase C and cerebral vasospasm

Twenty-five years after the discovery of protein kinase C (PKC), the physio logic function of PKC, and especially its role in pathologic conditions, re mains a subject of great interest with 30,000 studies published on these as pects. In the cerebral circulation, PKC plays a role in the regulation of m yogenic tone by sensitization of myofilaments to calcium. Protein kinase C phosphorylates various ion channels including augmenting voltage-dependent Ca2+ channels and inhibiting K+ channels, which both lead to vessel contrac tion. These actions of PKC amplify vascular reactivity to different agonist s and may be critical in the regulation of cerebral artery tone during vaso spasm. Evidence accumulated during at least the last decade suggest that ac tivation of PKC in cerebral vasospasm results in a delayed but prolonged co ntraction of major arteries after subarachnoid hemorrhage. Most of the expe rimental results in vitro or in animal models support the view that PKC is involved in cerebral vasospasm. Implication of PKC in cerebral vasospasm he lps explain increased arterial narrowing at the signal transduction level a nd alters current perceptions that the pathophysiology is caused by a combi nation of multiple receptor activation, hemoglobin toxicity, and damaged ne urogenic control. Activation of protein kinase C also interacts with other signaling pathways such as myosin light chain kinase, nitric oxide, intrace llular Ca2+, protein tyrosine kinase, and its substrates such as mitogen-ac tivated protein kinase. Even though identifying PKC revolutionized the unde rstanding of cerebral vasospasm, clinical advances are hampered by the lack of clinical trials using selective PKC inhibitors.