Protein kinase C and smooth muscle contraction

Protein kinase C (PKC) is a family of phospholipid-dependent Ca2+ diacylglycerol-stimulated enzymes. It is an ubiquitous protein that plays a multifunctional role in the transduction of extracellular signals activating the phospholipid turnover and generating diacylglycerol (DAG). DAG can be produced from the hydrolysis of phosphatidyl-inositol-1,4-bisphosphate, phosphatidylcholine, or sphingomyelin by respective phospholipases. PKC is also the major intracellular receptor for phorbol esters, potent tumor promoters, which may replace DAG for its activity. To date, 12 different PKC isoforms have been described, all regulated by phosphatidylserine and DAG, but only some being Ca2+-dependent (α, β1, β2, and γ). The δ1, δ2, δ3, e, η, θ, ι and ζ isoforms are Ca2+-independent. Each isoenzyme is a single polypeptide with four conserved (C1-C4) and five variable (V1-V5) regions. C1 and C2 regions constitute the regulatory domain and contain binding sites for phosphatidylserine, Ca2+, DAG, and phorbol esters, while C3 and C4 constitute the catalytic domain and contain binding sites for ATP, substrates, and various inhibitors. PKC isoenzymes are involved in a variety of cellular responses including growth, differentiation, neuronal development, synoptic transmission, secretion. They were first implicated in the regulation of smooth muscle contraction with the observation that phorbol esters induce slowly developing, sustained contractions. Both Ca2+-dependent (α, β) and Ca2+-independent (e) PKC isoforms have been identified in smooth muscle cells (SMC), and their involvement in the regulation of smooth muscle contractile state has been proved. Different isoenzymes may be activated by different contractile agonists in different SMC types. There are many potential targets for PKC in SMC that could play a role in the modulation of their contractily. Two actin filament-associated proteins, calponin and caldesmon, were shown to be substrates of PKC in SMC. They may regulate the interaction between actin and phosphorylated myosin. The phosphorylated calponin or caldesmon alleviate the inhibition of the cross-bridge cycling rate. Biomedical Reviews 1997; 8: 87-100.