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Different pathways for activation and deactivation in CaV1.2: a minimal gating model.

ABSTRACT: Point mutations in pore-lining S6 segments of CaV1.2 shift the voltage dependence of activation into the hyperpolarizing direction and significantly decelerate current activation and deactivation. Here, we analyze theses changes in channel gating in terms of a circular four-state model accounting for an activation R-A-O and a deactivation O-D-R pathway. Transitions between resting-closed (R) and activated-closed (A) states (rate constants x(V) and y(V)) and open (O) and deactivated-open (D) states (u(V) and w(V)) describe voltage-dependent sensor movements. Voltage-independent pore openings and closures during activation (A-O) and deactivation (D-R) are described by rate constants alpha and beta, and gamma and delta, respectively. Rate constants were determined for 16-channel constructs assuming that pore mutations in IIS6 do not affect the activating transition of the voltage-sensing machinery (x(V) and y(V)). Estimated model parameters of 15 CaV1.2 constructs well describe the activation and deactivation processes. Voltage dependence of the "pore-releasing" sensor movement ((x(V)) was much weaker than the voltage dependence of "pore-locking" sensor movement (y(V)). Our data suggest that changes in membrane voltage are more efficient in closing than in opening CaV1.2. The model failed to reproduce current kinetics of mutation A780P that was, however, accurately fitted with individually adjusted x(V) and y(V). We speculate that structural changes induced by a proline substitution in this position may disturb the voltage-sensing domain.

SUBMITTER: Beyl S

PROVIDER: S-EPMC2737230 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Different pathways for activation and deactivation in CaV1.2: a minimal gating model.

Beyl Stanislav S Kügler Philipp P Kudrnac Michaela M Hohaus Annette A Hering Steffen S Timin Eugen E

The Journal of general physiology 20090817 3

Point mutations in pore-lining S6 segments of CaV1.2 shift the voltage dependence of activation into the hyperpolarizing direction and significantly decelerate current activation and deactivation. Here, we analyze theses changes in channel gating in terms of a circular four-state model accounting for an activation R-A-O and a deactivation O-D-R pathway. Transitions between resting-closed (R) and activated-closed (A) states (rate constants x(V) and y(V)) and open (O) and deactivated-open (D) stat ...[more]

PMID: 19687230

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Project description:Activation of nuclear factor ?B (NF-?B) by interleukin-1? (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-?B dependent resynthesis of its own inhibitor I?B?. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-?B remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV-induced lack of I?B? recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of independent data. Weak constitutive IKK? phosphorylation is shown to be a decisive process in I?B? degradation induced by UVB stimulation alone, but irrelevant for (co-)stimulations with IL-1. In silico knockout experiments show that translational inhibition is predominantly responsible for lack of I?B? recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of I?B?. This shows that the processes leading to activation of transcription factor NF-?B upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting.

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Different pathways for activation and deactivation in CaV1.2: a minimal gating model.

Publications

Different pathways for activation and deactivation in CaV1.2: a minimal gating model.

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