DIRECT MODULATION OF NA-KINASE-C ACTIVATORS IN MOUSE NEUROBLASTOMA-CELLS( CURRENTS BY PROTEIN)

We investigated the effects of different protein kinase C (PKC) activa tors on Na+ currents using the conventional whole-cell and the inside- out macropatch voltage-clamp techniques in mouse neuroblastoma cells ( N1E-115). Two different categories of PRC activators were investigated : the cis-unsaturated fatty acids (CUFAs): oleic (cis-9-octadecenoic), linoleic (cis-P-12-octadecadienoic), and linolenic acid (cia-9-12-15- octadecatrienoic), and, the diacylglycerol (DAG) derivative 1-2-diocta noyl-sn-glycerol (DOG). These substances caused the following alterati ons on Na+ currents: (i) Na+ currents were attenuated as a function of voltage. While DOG attenuated both inward and outward Na+ currents in a monotonic and continuous voltage-dependent manner, CUFAs preferenti ally attenuated inward currents; (ii) the steady-state activation curv e of Na+ currents shifted to more depolarized voltages; (iii) opposite to the activation curve, the steady-state inactivation curve of Na+ c hannels (h curve) shifted to more hyperpolarized voltages; (iv) the ti me course of inactivation development was accelerated by PKC activator s, while the recovery from inactivation was not affected; (v) substanc es that inhibit different metabolic pathways (PKC activation, cyclooxy genase, lipooxygenase, and P-450 pathways) did not prevent the effects of PKC activators on Na+ currents. One fully saturated fatty acid (oc tadecanoic acid), a trans-unsaturated fatty acid (trans-9-octadecenoic ), and different phorbol esters did not affect Na+ currents; (vi) effe cts of different PKC activators on Na+ currents were completely revers ible. These observations suggest that PKC activators might interact wi th Na+ channels directly. These direct effects must be taken into cons ideration in evaluating the overall effect of PKC activation on Na+ ch annels, Moreover, it is likely that this direct interaction could acco unt, at least in part, for the diversity of effects of PKC activators on Na+ channels.