Low pH<sub>o</sub>boosts burst firing and catecholamine release by blocking TASK‐1 and BK channels while preserving Cav1 channels in mouse chromaffin cells

Guarina, Laura; Vandael, David; Carabelli, Valentina; Carbone, Emilio

doi:10.1113/jp273735

Cited by 31 publications

(64 citation statements)

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“…It has been reported that blood pH decreases to pH 6.9 when top athletes are maximally exercised (15). Thus, the present and the Guarina et al (17) findings indicate that TASK channels have an essential role for acidic detection in AM cells under physiologic conditions, such as exercise.…”

Section: Discussion K + Channels Involved In the Resting Membrane Potsupporting

confidence: 69%

“…Therefore, the molecular identity of TASK1-like channels in AM cells is indispensable in elucidating how the endocrine functions of AM cells are defined. In addition, besides TASK channels, large-conductance Ca 2+ -dependent K + (BK) channels have recently been suggested to be involved in pH decreaseinduced excitation in mouse AM cells (17). Thus, the present experiments were aimed at clarifying the involvement of BK channels in acidity-induced excitation and elucidating the molecular identity of TASK channels in mouse AM cells by using the genetic deletion of TASK channels.…”

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confidence: 99%

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Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells

et al. 2018

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External acidity induces catecholamine secretion by inhibiting TASK1-like channels in rat adrenal medullary (AM) cells. TASK channels can function as a heteromer or homomer in the TASK subfamily. In this study, we elucidate the molecular identity of TASK1-like channels in mouse AM cells using gene knockout. Genetic deletion of TASK1, but not TASK3, abolished the depolarizing inward current and catecholamine secretion in response to acidity, whereas it did not affect the resting current level. Immunocytochemistry revealed that AM cells exhibited predominantly TASK1-like and little TASK3-like immunoreactivity. A proximity ligation assay showed that TASK1/3 heteromeric channels were not formed in AM cells or PC12 cells. However, the exogenous expression of p11 in PC12 cells resulted in the heteromeric formation of TASK isoforms, which were mainly located in the cytoplasm, and p11 was not expressed in rat adrenal medullae or PC12 cells. In AM cells, genetic deletion of TASK1 resulted in enhancement of the immunoreactivity of the TALK2 channel, but not TASK3. The results indicate that TASK1 homomeric channels function as acidity sensors in AM cells, and that function is facilitated by the lack of p11 expression.-Inoue, M., Matsuoka, H., Lesage, F., Harada, K. Lack of p11 expression facilitates acidity-sensing function of TASK1 channels in mouse adrenal medullary cells.

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Section: Discussion K + Channels Involved In the Resting Membrane Potsupporting

confidence: 69%

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confidence: 99%

Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells

et al. 2018

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“…; Guarina et al . ). BK currents were obtained by first determining the contribution of K V currents to the total by adding 1 μM paxilline to block BK channels (Zhou & Lingle, ).…”

Section: Resultsmentioning

confidence: 97%

“… a , b ; Guarina et al . ; for a review see Lingle et al . ), specifically when (1) Na V channels are steadily inactivated, (2) K + ‐permeable channels (BK, TASK1‐3) are blocked, (3) inward L‐type currents are increased, or (4) following deletion of the BK‐β 2 subunit that completely abolishes BK channel inactivation.…”

Section: Discussionmentioning

confidence: 99%

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Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Calorio

Gavello

Guarina

et al. 2019

The Journal of Physiology

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Key points Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de novo point mutation in the gene encoding the Cav1.2 (CACNA1C) L‐type channel. To study the role of Cav1.2 channel signals in autism, the autistic TS2‐neo mouse has been generated bearing the G406R point‐mutation associated with TS type‐2. Using heterozygous TS2‐neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L‐type channels, causing marked increase of resting Ca2+ influx (‘window’ Ca2+ current). The increased ‘window current’ causes marked reduction of NaV channel density, switches normal tonic firing to abnormal burst firing, reduces mitochondrial metabolism, induces cell swelling and decreases catecholamine release. Overnight incubations with nifedipine rescue NaV channel density, normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cell malfunction derives from altered Cav1.2 channel gating. Abstract L‐type voltage‐gated calcium (Cav1) channels have a key role in long‐term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (CACNA1C) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type‐2 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6‐helix of the Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating‐changes alter cell excitability, neuronal firing and hormone release on a molecular basis is still largely unknown. Here, using the TS2‐neo mouse model of TS we show that the G406R mutation altered excitability and reduced secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2 mutation reduced the rate of voltage‐dependent inactivation and shifted leftward the activation and steady‐state inactivation of L‐type channels. This markedly increased the resting ‘window’ Ca2+ current that caused an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased ‘window’ Ca2+ current caused also decreased NaV channel density and increased steady‐state inactivation, which contributed to the increased abnormal burst firing. Overnight incubation with the L‐type channel blocker nifedipine rescued the normal AP firing of CCs, the density of functioning NaV channels and their steady‐state inactivation. We provide evidence that CC malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD.

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Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease

Carbone

Borges

Eiden

et al. 2019

Comprehensive Physiology

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Chromaffin cells (CCs) of the adrenal gland and the sympathetic nervous system produce the catecholamines (epinephrine and norepinephrine; EPI and NE) needed to coordinate the bodily "fight-or-flight" response to fear, stress, exercise, or conflict. EPI and NE release from CCs is regulated both neurogenically by splanchnic nerve fibers and nonneurogenically by hormones (histamine, corticosteroids, angiotensin, and others) and paracrine messengers [EPI, NE, adenosine triphosphate, opioids, γ-aminobutyric acid (GABA), etc.]. The "stimulus-secretion" coupling of CCs is a Ca 2+ -dependent process regulated by Ca 2+ entry through voltage-gated Ca 2+ channels, Ca 2+ pumps, and exchangers and intracellular organelles (RE and mitochondria) and diffusible buffers that provide both Ca 2+ -homeostasis and Ca 2+ -signaling that ultimately trigger exocytosis. CCs also express Na + and K + channels and ionotropic (nAChR and GABA A ) and metabotropic receptors (mACh, PACAP, β-AR, 5-HT, histamine, angiotensin, and others) that make CCs excitable and responsive to autocrine and paracrine stimuli. To maintain high rates of E/NE secretion during stressful conditions, CCs possess a large number of secretory chromaffin granules (CGs) and members of the soluble NSF-attachment receptor complex protein family that allow docking, fusion, and exocytosis of CGs at the cell membrane, and their recycling. This article attempts to provide an updated account of well-established features of the molecular processes regulating CC function, and a survey of the as-yet-unsolved but important questions relating to CC function and dysfunction that have been the subject of intense research over the past 15 years. Examples of CCs as a model system to understand the molecular mechanisms associated with neurodegenerative diseases are also provided.

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Low pH_oboosts burst firing and catecholamine release by blocking TASK‐1 and BK channels while preserving Cav1 channels in mouse chromaffin cells

Cited by 31 publications

References 64 publications

Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells

Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease

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Low pHoboosts burst firing and catecholamine release by blocking TASK‐1 and BK channels while preserving Cav1 channels in mouse chromaffin cells

Cited by 31 publications

References 64 publications

Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells

Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease

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Low pH_oboosts burst firing and catecholamine release by blocking TASK‐1 and BK channels while preserving Cav1 channels in mouse chromaffin cells