Pannexin 1 Regulates Dendritic Protrusion Dynamics in Immature Cortical Neurons

Sanchez-Arias, Juan C.; Candlish, Rebecca C.; Slagt, Emma van der; Swayne, Leigh Anne

doi:10.1523/eneuro.0079-20.2020

Cited by 16 publications

(12 citation statements)

References 60 publications

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“…Panx1 activation has been linked to pathophysiological disorders, such as excitotoxicity, stroke, migraine, chronic pain, and epilepsy ( 16 – 18 ). However, Panx1 also mediates physiological processes in the CNS, including contributions to neural development ( 19 , 20 ), spine formation ( 21 , 22 ), and NMDAR-dependent synaptic plasticity ( 23 , 24 ). In this context, there remains an important gap in understanding the mechanisms by which Panx1 can mediate such disparate physiological and pathological functions.…”

mentioning

confidence: 99%

ER-resident STIM1/2 couples Ca ²⁺ entry by NMDA receptors to pannexin-1 activation

Patil

Lavine

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca 2+ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus–recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca 2+ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.

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confidence: 99%

ER-resident STIM1/2 couples Ca ²⁺ entry by NMDA receptors to pannexin-1 activation

Patil

Lavine

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Another key aspect to link PANX1 and cell migration is the direct association between PANX channels and cytoskeletal components (actin, MyoII, microtubules), which are master regulators of cell migration. There is evidence of direct and indirect modulation of PANX channels by the cytoskeleton, which modifies membrane dynamics ( 144 ). In addition, PANX1 channels are somehow mechanosensitive, although in a lesser extent in comparison to other channels such as Piezo1 and Piezo2 ( 145 ).…”

Section: Discussionmentioning

confidence: 99%

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells

et al. 2021

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The role of Pannexin (PANX) channels during collective and single cell migration is increasingly recognized. Amongst many functions that are relevant to cell migration, here we focus on the role of PANX-mediated adenine nucleotide release and associated autocrine and paracrine signaling. We also summarize the contribution of PANXs with the cytoskeleton, which is also key regulator of cell migration. PANXs, as mechanosensitive ATP releasing channels, provide a unique link between cell migration and purinergic communication. The functional association with several purinergic receptors, together with a plethora of signals that modulate their opening, allows PANX channels to integrate physical and chemical cues during inflammation. Ubiquitously expressed in almost all immune cells, PANX1 opening has been reported in different immunological contexts. Immune activation is the epitome coordination between cell communication and migration, as leukocytes (i.e., T cells, dendritic cells) exchange information while migrating towards the injury site. In the current review, we summarized the contribution of PANX channels during immune cell migration and recruitment; although we also compile the available evidence for non-immune cells (including fibroblasts, keratinocytes, astrocytes, and cancer cells). Finally, we discuss the current evidence of PANX1 and PANX3 channels as a both positive and/or negative regulator in different inflammatory conditions, proposing a general mechanism of these channels contribution during cell migration.

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“…Precise regulation of purinergic signalling via PANX1 is critical in many diverse cell types, including maintaining neural stem cell populations [76–78], regulating the development of immature neurons [79,80], tumorigenicity [81,82] and metastasis [83] of several cancers [84]. Macropinocytosis is also intimately involved in regulating these processes ([3–11], reviewed in Finicle et al [12] and Bloomfield and Kay [13]).…”

Section: Discussionmentioning

confidence: 99%

ATP triggers macropinocytosis that internalizes and is regulated by PANX1

Boyce

Slagt

Sanchez-Arias

et al. 2020

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Macropinocytosis is an endocytic process that allows cells to respond to changes in their environment by internalizing nutrients and cell surface proteins, as well as modulating cell size. Here, we identify that adenosine triphosphate (ATP) triggers macropinocytosis in murine neuroblastoma cells, thereby internalizing the ATP release channel pannexin 1 (PANX1) while concurrently increasing cross-sectional cellular area. Amiloride, a potent inhibitor of macropinocytosis-associated GTPases, abolished ATP-induced PANX1 internalization and cell area expansion. Transient expression of the GTP-hydrolysis resistant GTPase ARF6 Q67L led to increased PANX1 internalization and increased cell area equivalent to levels seen with ATP stimulation. Mutation of an extracellular tryptophan (W74) in PANX1 abolished ATP-evoked cell area enlargement suggesting that PANX1 regulates this form of macropinocytosis. This novel role of PANX1 in macropinocytosis could be particularly important for disease states implicating PANX1, such as cancer, where ATP can act as a purinergic regulator of cell growth/metastasis and as a supplementary energy source following internalization.

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Pannexin 1 Regulates Dendritic Protrusion Dynamics in Immature Cortical Neurons

Abstract: Pannexin 1 regulates dendritic protrusion dynamics in immature cortical neurons

Cited by 16 publications

References 60 publications

ER-resident STIM1/2 couples Ca ²⁺ entry by NMDA receptors to pannexin-1 activation

ER-resident STIM1/2 couples Ca ²⁺ entry by NMDA receptors to pannexin-1 activation

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells

ATP triggers macropinocytosis that internalizes and is regulated by PANX1

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Pannexin 1 Regulates Dendritic Protrusion Dynamics in Immature Cortical Neurons

Abstract: Pannexin 1 regulates dendritic protrusion dynamics in immature cortical neurons

Cited by 16 publications

References 60 publications

ER-resident STIM1/2 couples Ca 2+ entry by NMDA receptors to pannexin-1 activation

ER-resident STIM1/2 couples Ca 2+ entry by NMDA receptors to pannexin-1 activation

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells

ATP triggers macropinocytosis that internalizes and is regulated by PANX1

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ER-resident STIM1/2 couples Ca ²⁺ entry by NMDA receptors to pannexin-1 activation

ER-resident STIM1/2 couples Ca ²⁺ entry by NMDA receptors to pannexin-1 activation