Down-regulation of endogenous KLHL1 decreases voltage-gated calcium current density

Perissinotti, Paula P.; Ethington, Elizabeth G.; Cribbs, Leanne L.; Koob, Michael D.; Martin, J.L.; Piedras-Renterı́a, Erika S.

doi:10.1016/j.ceca.2014.03.002

Cited by 17 publications

(30 citation statements)

References 60 publications

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“…Similar observations were made upon disruption of endosomal recycling suggesting that KLHL1 enhances surface expression of T-type channels by potentiating their re-insertion into the plasma membrane from recycling endosomes (Figure 3) [120]. The role of KLHL1 in the expression of VGCCs in further supported by the observation that shRNA knockdown of KLHL1 in hippocampal neurons in culture caused a dramatic decrease in both HVA and LVA Ca 2 + currents [122]. These results are consistent with the observation that Ca v 2.1 and Ca v 3.2 are down-regulated in hippocampal neurons from KLHL1 KO mice [123].…”

Section: Kelch-likesupporting

confidence: 64%

Trafficking of neuronal calcium channels

Weiss

Zamponi

2017

Neuronal Signaling

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Neuronal voltage-gated calcium channels (VGCCs) serve complex yet essential physiological functions via their pivotal role in translating electrical signals into intracellular calcium elevations and associated downstream signalling pathways. There are a number of regulatory mechanisms to ensure a dynamic control of the number of channels embedded in the plasma membrane, whereas alteration of the surface expression of VGCCs has been linked to various disease conditions. Here, we provide an overview of the mechanisms that control the trafficking of VGCCs to and from the plasma membrane, and discuss their implication in pathophysiological conditions and their potential as therapeutic targets.

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Section: Kelch-likesupporting

confidence: 64%

Trafficking of neuronal calcium channels

Weiss

Zamponi

2017

Neuronal Signaling

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“…Cell Culture: Whole hypothalamus were dissected from newborn mice (P0) and cultured as described in (P. P. Perissinotti et al, 2014) and plated at a density of 25,000-35,000/coverslip and kept in a 5% CO2 humidified atmosphere at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…WT neurons at 9-11 DIV were prepared as described (P. P. Perissinotti et al, 2014). Primary antibody dilutions were: POMC 1:200 (Novus); AgRP, 1:200 (Sta.…”

Section: Immunocytochemistry (Ic)mentioning

confidence: 99%

TRPC5-Ca_V3 complex mediates Leptin-induced excitability in hypothalamic neurons

Perissinotti

Martínez-Hernández

Piedras-Renterı́a

2020

Preprint

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Leptin regulates hypothalamic POMC+ (pro-opiomelanocortin) neurons by inducing TRPC (Transient Receptor Potential Cation) channel-mediate membrane depolarization. Here we assessed the role of T-type channels on POMC neuron excitability and leptin-induced depolarization in vitro. We demonstrate T-type currents are indispensable for both processes, as treatment with NNC-55-0396 prevented the membrane depolarization and rheobase changes induced by leptin in cultured mouse POMC neurons. Furthermore, we demonstrate TRPC1/C5 channels and CaV3.1 and CaV3.2 channels co-exist in complex. The functional relevance of this complex was corroborated using intracellular Ca2+ chelators; intracellular BAPTA (but not EGTA) application was sufficient to preclude POMC neuron excitability by preventing leptin-induced calcium influx through TRPC channels and T-type channel function.We conclude T-type channels are integral in POMC neuron excitability. Leptin activation of TRPC channels existing in a macromolecular complex with T-type channels recruits the latter by locally-induced membrane depolarization, further depolarizing POMC neurons, triggering action potentials and excitability.

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“… Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated Ca V 2.1 (P/Q-type) and Ca V 3.2 (α 1H T-type) calcium channels; KLHL1 knockdown experiments (KD) cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al, 2014 ). Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO) mice.…”

mentioning

confidence: 99%

Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

Perissinotti

Ethington

Almazan

et al. 2015

Front. Cell. Neurosci.

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Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type) and CaV3.2 (α1H T-type) calcium channels; KLHL1 knockdown experiments (KD) cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014). Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO) mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT); and P/Q-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were also reduced in the KO hippocampus and cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC) frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

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Down-regulation of endogenous KLHL1 decreases voltage-gated calcium current density

Cited by 17 publications

References 60 publications

Trafficking of neuronal calcium channels

Trafficking of neuronal calcium channels

TRPC5-Ca_V3 complex mediates Leptin-induced excitability in hypothalamic neurons

Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

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Down-regulation of endogenous KLHL1 decreases voltage-gated calcium current density

Cited by 17 publications

References 60 publications

Trafficking of neuronal calcium channels

Trafficking of neuronal calcium channels

TRPC5-CaV3 complex mediates Leptin-induced excitability in hypothalamic neurons

Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

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Product

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TRPC5-Ca_V3 complex mediates Leptin-induced excitability in hypothalamic neurons