Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase

Abstract

The function of voltage-gated sodium channels that are responsible for action potential generation in mammalian brain neurons is modulated by phosphorylation by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (cA-PK) and by protein kinase C (PKC). Reduction of peak sodium currents by cA-PK in intact cells required concurrent activation of PKC and was prevented by blocking phosphorylation of serine 1506, a site in the inactivation gate of the channel that is phosphorylated by PKC but not by cA-PK. Replacement of serine 1506 with negatively charged amino acids mimicked the effect of phosphorylation. Conversion of the consensus sequence surrounding serine 1506 to one more favorable for cA-PK enhanced modulation of sodium currents by cA-PK. Convergent modulation of sodium channels required phosphorylation of serine 1506 by PKC accompanied by phosphorylation of additional sites by cA-PK. This regulatory mechanism may serve to integrate neuronal signals mediated through these parallel signaling pathways.

Dual role of protein kinase C on BK channel regulation

“…Reduced G max could not be reversed by increasing voltage or Ca 2+ . The inhibitory PKC effect was abolished when inside-out patches were concurrently superfused for at least 5 min with PKC c and 5 μM of the PKC pseudosubstrate inhibitor peptide PKC [19][20][21][22][23][24][25][26][27][28][29][30][31] (Fig. 1A).…”

“…To allow complete dephosphorylation of PKC sites, inside-out patches were first superfused for 5 min with ATP-free solution to which 5 μM PKC [19][20][21][22][23][24][25][26][27][28][29][30][31] had been added. This solution, which did not significantly alter NP o , was then changed for another 5 min to a solution containing ATP, PKC [19][20][21][22][23][24][25][26][27][28][29][30][31] , and either PKG or PKA. Similar to the results obtained with the mutant BK channel S 1151 A (Fig.…”

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α 1A subunit

“…Complex regulatory interactions among L I-II , Ca␤, and G␤␥ may be expected to provide subtle regulation of channel properties. Interestingly, the corresponding intracellular loop of Na ϩ channels contains a family of phosphorylation sites for cAMP-dependent protein kinase and protein kinase C which also modulate channel function (27), indicating that this loop serves a modulatory function in the structurally related Na ϩ channel ␣ subunit as well.…”

Using Evolutionary Algorithms to Search for Control Parameters in a Nonlinear Partial Differential Equation

“…In such a case, the rate of improvement is reduced to that of a random walk search. However, an extremely large population could increase the amount of computer time needed to solve the problem and might not improve the rate at which the problem is solved (Macready et al 1996). Initialization The initial parameters were randomly selected and scaled as follows: 1) 114 real-valued random numbers were drawn between 0 and 1; 2) a random number was selected between 0.5 and 2.0 to scale the excitatory-toinhibitory conductance ratio; and 3) a random number between 0 and 2,500 mS/cm 2 was selected to scale the total conductance.…”

“…The contribution of VGCD channel subtypes to information encoding varies adaptively, however. Intracellular signaling compounds, whose concentrations are elevated in response to activity, functionally modulate the kinetics and maximum conductances of VGCD channels (Perezreyes and Schneider 1994, Kallen et al 1993, Li et al 1993, Toro and Stefani 1991, Numann et al 1991, Chetkovich et al 1991. A significant body of work in Aplysia suggests that some forms of animal learning can be attributed to the activity-dependent modulations of VGCD channels (Klein and Kandel 1978, Fitzgerald et al 1990, Edmonds et al 1990.…”