Neuroscience_topics
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Neuroscience_topics
Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Scooped by Julien Hering, PhD
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The Cav3–Kv4 Complex Acts as a Calcium Sensor to Maintain Inhibitory Charge Transfer during Extracellular Calcium Fluctuations

Synaptic transmission and neuronal excitability depend on the concentration of extracellular calcium ([Ca]o), yet repetitive synaptic input is known to decrease [Ca]oin numerous brain regions. In the cerebellar molecular layer, synaptic input reduces [Ca]o by up to 0.4 mM in the vicinity of stellate cell interneurons and Purkinje cell dendrites. The mechanisms used to maintain network excitability and Purkinje cell output in the face of this rapid change in calcium gradient have remained an enigma. Here we use single and dual patch recordings in an in vitro slice preparation of Sprague Dawley rats to investigate the effects of physiological decreases in [Ca]o on the excitability of cerebellar stellate cells and their inhibitory regulation of Purkinje cells. We find that a Cav3–Kv4 ion channel complex expressed in stellate cells acts as a calcium sensor that responds to a decrease in [Ca]o by dynamically adjusting stellate cell output to maintain inhibitory charge transfer to Purkinje cells. The Cav3–Kv4 complex thus enables an adaptive regulation of inhibitory input to Purkinje cells during fluctuations in [Ca]o, providing a homeostatic control mechanism to regulate Purkinje cell excitability during repetitive afferent activity. (...) - by Anderson D & Engbers JDT et al.The Journal of Neuroscience, 1 May 2013, 33(18): 7811-7824

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Scooped by Julien Hering, PhD
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Ligand-Gating by Ca2+ Is Rate Limiting for Physiological Operation of BKCa Channels

Large conductance Ca2+- and voltage-activated potassium channels (BKCa) shape neuronal excitability and signal transduction. This reflects the integrated influences of transmembrane voltage and intracellular calcium concentration ([Ca2+]i) that gate the channels. This dual gating has been mainly studied as voltage-triggered gating modulated by defined steady-state [Ca2+]i, a paradigm that does not approximate native conditions. Here we use submillisecond changes of [Ca2+]i to investigate the time course of the Ca2+-triggered gating of BKCa channels expressed in Chinese hamster ovary cells at distinct membrane potentials in the physiological range. The results show that Ca2+ can effectively gate BKCa channels and that Ca2+ gating is largely different from voltage-driven gating. Most prominently, Ca2+ gating displays a pronounced delay in the millisecond range between Ca2+ application and channel opening (pre-onset delay) and exhibits slower kinetics across the entire [Ca2+]i-voltage plane. Both characteristics are selectively altered by co-assembled BKβ4 or an epilepsy-causing mutation that either slows deactivation or speeds activation and reduces the pre-onset delay, respectively. Similarly, co-assembly of the BKCachannels with voltage-activated Ca2+ (Cav) channels, mirroring the native configuration, decreased the pre-onset delay to submillisecond values. In BKCa–Cav complexes, the time course of the hyperpolarizing K+-current response is dictated by the Ca2+ gating of the BKCa channels. Consistent with Cav-mediated Ca2+ influx, gating was fastest at hyperpolarized potentials, but decreased with depolarization of the membrane potential. Our results demonstrate that under experimental paradigms meant to approximate the physiological conditions BKCa channels primarily operate as ligand-activated channels gated by intracellular Ca2+ and that Ca2+ gating is tuned for fast responses in neuronal BKCa–Cav complexes. - by Berkefeld H & Fakler B, The Journal of Neuroscience, 24 April 2013, 33(17): 7358-7367

Julien Hering, PhD's insight:

The BKca channels are directly tuned by intracellular calcium binding. These channels are fast-operated by variation of intracellular calcium in physiological conditions through the BKca-Cav complexes.

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