Previously we demonstrated that insulin-like growth factor-I mediates the sustained phosphorylation of Akt, which is essential for long term survival and protection of glial progenitors from glutamate toxicity. These prosurvival effects correlated with prolonged activation and stability of the insulin-like growth factor type-I receptor. In the present study, we investigated the mechanisms whereby insulin-like growth factor-I signaling, through the insulin-like growth factor type-I receptor, mediates the sustained phosphorylation of Akt. We showed that insulin-like growth factor-I stimulation induced loss of receptors from the cell surface but that surface receptors recovered over time. Blocking receptor internalization inhibited Akt phosphorylation, whereas inhibition of receptor trafficking blocked receptor recovery at the cell surface and the sustained phosphorylation of Akt. Moreover the insulin-like growth factor type-I receptor localized with the transferrin receptor and Rab11-positive endosomes in a ligand-dependent manner, further supporting the conclusion that this receptor follows a recycling pathway. Our results provide evidence that ligand stimulation leads to internalization of the insulin-like growth factor type-I receptor, which mediates Akt phosphorylation, and that receptor recycling sustains Akt phosphorylation in glial progenitors. Mathematical modeling of receptor trafficking further supports these results and predicts an additional kinetic state of the receptor consistent with sustained Akt phosphorylation.

Gonadotropin-releasing hormone (GnRH) secretion from native and immortalized hypothalamic neurons is regulated by endogenous Ca 2ϩ -mobilizing and adenylyl cyclase (AC)-coupled receptors. Activation of both receptor types leads to an increase in action potential firing frequency and a rise in the intracellular pool mimics the receptor-induced activation of I SOC and I SK , leading to an increase in the firing frequency and Ca 2ϩ influx after a transient cessation of electrical activity. However, increasing the activity of I d simulates the experimental response to forskolin-induced activation of AC. Analysis of the behaviors of I SOC , I d , and I SK in the model reveals the complexity in the interplay of these currents that is necessary to fully account for the experimental results.

We study a recently discovered class of models for plateau bursting, inspired by models for endocrine pituitary cells. In contrast to classical models for fold-homoclinic (square-wave) bursting, the spikes of the active phase are not supported by limit cycles of the frozen fast subsystem, but are transient oscillations generated by unstable limit cycles emanating from a subcritical Hopf bifurcation around a stable steady state. Experimental time courses are suggestive of such fold-subHopf models because the spikes tend to be small and variable in amplitude; we call this pseudo-plateau bursting. We show here that distinct properties of the response to attempted resets from the silent phase to the active phase provide a clearer, qualitative criterion for choosing between the two classes of models. The fold-homoclinic class is characterized by induced active phases that increase towards the duration of the unperturbed active phase as resets are delivered later in the silent phase. For the fold-subHopf class of pseudo-plateau bursting, resetting is difficult and succeeds only in limited windows of the silent phase but, paradoxically, can dramatically exceed the native active phase duration.

Corticotropin-releasing hormone (CRH) is an important regulator of adrenocorticotropin (ACTH) secretion from pituitary corticotroph cells. The intracellular signaling system that underlies this process involves modulation of voltage-sensitive Ca2+ channel activity, which leads to the generation of Ca2+ action potentials and influx of Ca2+. However, the mechanisms by which Ca2+ channel activity is modulated in corticotrophs are not currently known. We investigated this process in a Hodgkin-Huxley-type mathematical model of corticotroph plasma membrane electrical responses. We found that an increase in the L-type Ca2+ current was sufficient to generate action potentials from a previously resting state of the model. The increase in the L-type current could be elicited by either a shift in the voltage dependence of the current toward more negative potentials, or by an increase in the conductance of the current. Although either of these mechanisms is potentially responsible for the generation of action potentials, previous experimental evidence favors the former mechanism, with the magnitude of the shift required being consistent with the experimental findings. The model also shows that the T-type Ca2+ current plays a role in setting the excitability of the plasma membrane, but does not appear to contribute in a dynamic manner to action potential generation. Inhibition of a K+ conductance that is active at rest also affects the excitability of the plasma membrane.