Non-conventional Axonal Organelles Control TRPM8 Ion Channel Trafficking and Peripheral Cold Sensing

Cornejo, Víctor Hugo; González, César; Campos, Matías; Vargas-Saturno, Leslie; Juricic, Maria; Miserey-Lenkei, Stéphanie; Pertusa, Marı́a; Madrid, Rodolfo; Couve, Andrés

doi:10.1016/j.celrep.2020.03.017

Cited by 19 publications

(19 citation statements)

References 73 publications

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“…As a first approach, we used Ca 2+ -imaging, a non-invasive technique that avoids a potential disruption of cell-signaling pathways. HEK-293 cells stably expressing mTRPM8-myc channels (HEK-293-mTRPM8-myc) [ 52 ] were preincubated for 10 min at 37 °C with extracellular solution containing 1 µM of PMA, or with control solution ( Figure 1 ). To exclude the direct effects of PMA on TRPM8 channels, we also tested the effect of the biologically inactive analog 4α-PMA at the same concentration as the active compound.…”

Section: Resultsmentioning

confidence: 99%

“…It is known that the TRPM8 channel travels to the plasma membrane of primary sensory neurons in atypical secretory vesicles with lysosomal-associated membrane protein 1 (LAMP1) and RAB7 molecular identity [ 63 ]. Recently, we also described a non-conventional trafficking mechanism involved in the recycling of TRPM8 channels to the plasma membrane in sensory fibers, with an important role in peripheral cold sensing [ 52 ]. Our present findings suggest that PKC could alter TRPM8 trafficking, as is the case for several ion channels and transporters [ 64 , 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

“…A HEK-293 cell line stably expressing mouse TRPM8-myc channels (HEK-293-mTRPM8-myc cells) [ 52 ] was used in this study. This cell line was cultured in DMEM containing 10% fetal bovine serum and 600 µg/mL geneticin.…”

Section: Methodsmentioning

confidence: 99%

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Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Rivera

Campos

Orio

et al. 2020

IJMS

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TRPM8 is the main molecular entity responsible for cold sensing. This polymodal ion channel is activated by cold, cooling compounds such as menthol, voltage, and rises in osmolality. In corneal cold thermoreceptor neurons (CTNs), TRPM8 expression determines not only their sensitivity to cold, but also their role as neural detectors of ocular surface wetness. Several reports suggest that Protein Kinase C (PKC) activation impacts on TRPM8 function; however, the molecular bases of this functional modulation are still poorly understood. We explored PKC-dependent regulation of TRPM8 using Phorbol 12-Myristate 13-Acetate to activate this kinase. Consistently, recombinant TRPM8 channels, cultured trigeminal neurons, and free nerve endings of corneal CTNs revealed a robust reduction of TRPM8-dependent responses under PKC activation. In corneal CTNs, PKC activation decreased ongoing activity, a key parameter in the role of TRPM8-expressing neurons as humidity detectors, and also the maximal cold-evoked response, which were validated by mathematical modeling. Biophysical analysis indicated that PKC-dependent downregulation of TRPM8 is mainly due to a decreased maximal conductance value, and complementary noise analysis revealed a reduced number of functional channels at the cell surface, providing important clues to understanding the molecular mechanisms of how PKC activity modulates TRPM8 channels in CTNs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Rivera

Campos

Orio

et al. 2020

IJMS

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“…Finally, an outstanding article shows the experimental evidence in vitro and in vivo on the regulation of TRPM8 trafficking by axonal organelles and its crucial role for the cold sensation and transduction in peripheral axons [114]. The authors demonstrated the implication of the ARF-GEF Golgi-specific brefeldin A-resistance factor 1 (GBF1) through the inhibition of GBF1 in axons of the sciatic nerve and corneal cold thermoreceptors in vivo.…”

Section: Trpm8 Distribution and Pathological Implicationmentioning

confidence: 99%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

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“…However, to date, Golgi structures have been identified in dendrites, and not in axons, in the central nervous system (CNS). In peripheral neurons, Golgi structures have been detected in both the dendrites (see below) and also recently in axons (Cornejo et al, 2020). Given the importance of the Golgi apparatus in post-translational modifications and anterograde transport of newly synthesized soluble and membrane proteins, more extensive studies have been carried out on the local secretory systems of dendrites compared with axons and, therefore, this review will focus on the local secretory organelles of dendrites.…”

Section: Introductionmentioning

confidence: 99%

Local Secretory Trafficking Pathways in Neurons and the Role of Dendritic Golgi Outposts in Different Cell Models

Wang

Fourrière

Gleeson

2020

Front. Mol. Neurosci.

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A fundamental characteristic of neurons is the relationship between the architecture of the polarized neuron and synaptic transmission between neurons. Intracellular membrane trafficking is paramount to establish and maintain neuronal structure; perturbation in trafficking results in defects in neurodevelopment and neurological disorders. Given the physical distance from the cell body to the distal sites of the axon and dendrites, transport of newly synthesized membrane proteins from the central cell body to their functional destination at remote, distal sites represents a conundrum. With the identification of secretory organelles in dendrites, including endoplasmic reticulum (ER) and Golgi outposts (GOs), recent studies have proposed local protein synthesis and trafficking distinct from the conventional anterograde transport pathways of the cell body. A variety of different model organisms, including Drosophila, zebrafish, and rodents, have been used to probe the organization and function of the local neuronal secretory network. Here, we review the evidence for local secretory trafficking pathways in dendrites in a variety of cell-based neuronal systems and discuss both the similarities and differences in the organization and role of the local secretory organelles, especially the GOs. In addition, we identify the gaps in the current knowledge and the potential advances using human induced pluripotent stem cells (iPSCs) in defining local membrane protein trafficking in human neurons and in understanding the molecular basis of neurological diseases.

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Non-conventional Axonal Organelles Control TRPM8 Ion Channel Trafficking and Peripheral Cold Sensing

Abstract: Highlights d TRPM8 nerve trafficking depends on a non-conventional axonal secretory route d GBF1 and RAB6 interaction orchestrate axonal Golgi satellites in nerve fibers d Local disruption of axonal secretory organelles affects TRPM8 cold sensing in mice

Cited by 19 publications

References 73 publications

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Local Secretory Trafficking Pathways in Neurons and the Role of Dendritic Golgi Outposts in Different Cell Models

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