Can the Ca2+ hypothesis and the Ca2+-voltage hypothesis for neurotransmitter release be reconciled?

It is well established that Ca2+ plays a key role in promoting the physiological depolarization-induced release (DIR) of neurotransmitters from nerve terminals (Ca2+ hypothesis). Yet, evidence has accumulated for the Ca2+-voltage hypothesis, which states that not only is Ca2+ required, but membrane potential as such also plays a pivotal role in promoting DIR. An essential aspect of the Ca2+-voltage hypothesis is that it is depolarization that is responsible for the initiation of release. This assertion seems to be contradicted by recent experiments wherein release was triggered by high concentrations of intracellular Ca2+ in the absence of depolarization [calcium-induced release (CIR)]. Here we show that there is no contradiction between CIR and the Ca2+-voltage hypothesis. Rather, CIR can be looked at as a manifestation of spontaneous release under conditions of high intracellular Ca2+ concentration. Spontaneous release in turn is governed by a subset of the molecular scheme for DIR, under conditions of no depolarization. Prevailing estimates for the intracellular calcium concentration, [Ca2+]i, in physiological DIR rely on experiments under conditions of CIR. Our theory suggests that these estimates are too high, because depolarization is absent in these experiments and [Ca2+]i is held at high levels for an extended period.

How instruction and feedback can select the appropriate T helper response.

The decision of the immune system to trigger immune responses that are, respectively, induced by Th1 or Th2 effectors is a critical one, because it profoundly influences disease outcome. We have recently constructed a mathematical model of Th1-Th2-pathogen interactions that shows that the major decisional events can often be successfully determined by the intrinsic behaviour of the T helper system itself. For certain dangerous types of pathogens, however, which replicate rapidly or have developed strategies to evade the immune response, additional stimuli may be necessary. As a possible mechanism for the decision-making process innate immune recognition has been proposed. Here we present an enlarged version of our model, which incorporates signals created from the innate immune system after pathogen recognition. The model analysis suggests that there is fault-tolerance of the T helper system to incorrect Th1 signals. In the presence of incorrect Th1 stimuli an initial Th1 response is shifted to the correct Th2-dominated response owing to the intrinsic T helper dynamics. By contrast, according to our model there is no fault-tolerance for incorrect Th2 signals. In fact, if timing is unimportant then Th2 signals are superfluous since the intrinsic T helper dynamics provide an automatic switch to Th2 if Th1 effectors fail to control the pathogen. Th2 signals may, however, be required to accelerate the onset of the Th2 response. Additionally, we discuss the role of feedback where successful pathogen destruction leads to up-regulation of activation of the effective T helper type. As one possibility we examine the role of CpG motifs as indicators for successful pathogen destruction. Differences between instructive and feedback mechanisms are highlighted.