MODULATION OF RAT SKELETAL MUSCLE CHLORIDE CHANNELS BY ACTIVATORS AND INHIBITORS OF PROTEIN KINASE C

The membrane electrical parameters and component conductances of rat extensor digitorum longus muscle fibres were studied in vitro at 30-degrees-C with standard two microelectrode square pulse cable analysis in the presence of protein kinase C (PKC) activators and inhibitors. The PKC activator, 4-beta-phorbol-12,13 dibutyrate (4-beta-PDB), (2-90 nM) blocked up to 67% chloride conductance (G(Cl)) in rat skeletal muscle fibres and induced myotonic hyperexcitability. The concentration necessary to produce a 50% block of the membrane G(Cl) was 23 nM. The "inactive" 4-alpha-phorbol-12,13 dibutyrate had no effect at 2-mu-M. The blocking effect of 4-beta-PDB on G(Cl) was prevented by preincubation of the preparations with the PKC inhibitors, staurosporine (1 - 5-mu-M) and tetrahydropapaverolone (50 - 100-mu-M). The blocking effects on membrane G(Cl) of 4-beta-PDB and its antagonism by the inhibitors used support the concept of the involvement of PKC in regulating Cl channels of mammalian skeletal muscle fibres.