Ca²⁺-Dependent and Na⁺-Dependent K⁺ Conductances Contribute to a Slow AHP in Thalamic Paraventricular Nucleus Neurons: A Novel Target for Orexin Receptors

3区 · 医学

Article

作者: Renaud, Leo P. ; Kolaj, Miloslav ; Zhang, Li

Thalamic paraventricular nucleus (PVT) neurons exhibit a postburst apamin-resistant slow afterhyperpolarization (sAHP) that is unique to midline thalamus, displays activity dependence, and is abolished in tetrodotoxin. Analysis of the underlying s IAHP confirmed a requirement for Ca2+ influx with contributions from P/Q-, N-, L-, and R subtype channels, a reversal potential near EK+ and a significant reduction by UCL-2077, barium or TEA, consistent with a role for KCa channels. s IAHP was significantly reduced by activation of either the cAMP or the protein kinase C (PKC) signaling pathway. Further analysis of the sAHP revealed an activity-dependent but Ca2+-independent component that was reduced in high [K+]o and blockable after Na+ substitution with Li+ or in the presence of quinidine, suggesting a role for KNa channels. The Ca2+-independent sAHP component was selectively reduced by activation of the PKC signaling pathway. The sAHP contributed to spike frequency adaptation, which was sensitive to activation of either cAMP or PKC signaling pathways and, near the peak of membrane hyperpolarization, was sufficient to cause de-inactivation of low threshold T-Type Ca2+ channels, thus promoting burst firing. PVT neurons are densely innervated by orexin-immunoreactive fibers, and depolarized by exogenously applied orexins. We now report that orexin A significantly reduced both Ca2+-dependent and -independent s IAHP, and spike frequency adaptation. Furthermore orexin A-induced s IAHP inhibition was mediated through activation of PKC but not PKA. Collectively, these observations suggest that KCa and KNa channels have a role in a sAHP that contributes to spike frequency adaptation and neuronal excitability in PVT neurons and that the sAHP is a novel target for modulation by the arousal- and feeding-promoting orexin neuropeptides.

Frontiers in Cellular Neuroscience

Vasoactive intestinal peptide excites GnRH neurons via KCa3.1, a potential player in the slow afterhyperpolarization current

Article

作者: Constantin, Stephanie ; Wray, Susan ; Quignon, Clarisse ; Shostak, David M ; Pizano, Katherine

Vasoactive intestinal peptide (VIP) is an important component of the suprachiasmatic nucleus (SCN) which relays circadian information to neuronal populations, including GnRH neurons. Human and animal studies have shown an impact of disrupted daily rhythms (chronic shift work, temporal food restriction, clock gene disruption) on both male and female reproduction and fertility. To date, how VIP modulates GnRH neurons remains unknown. Calcium imaging and electrophysiology on primary GnRH neurons in explants and adult mouse brain slice, respectively, were used to address this question. We found VIP excites GnRH neurons via the VIP receptor, VPAC2. The downstream signaling pathway uses both Gs protein/adenylyl cyclase/protein kinase A (PKA) and phospholipase C/phosphatidylinositol 4,5-bisphosphate (PIP2) depletion. Furthermore, we identified a UCL2077-sensitive target, likely contributing to the slow afterhyperpolarization current (IAHP), as the PKA and PIP2 depletion target, and the KCa3.1 channel as a specific target. Thus, VIP/VPAC2 provides an example of Gs protein-coupled receptor-triggered excitation in GnRH neurons, modulating GnRH neurons likely via the slow IAHP. The possible identification of KCa3.1 in the GnRH neuron slow IAHP may provide a new therapeutical target for fertility treatments.

100 项与 UCL2077 相关的药物交易

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