Antagonism of TRPV4 channels partially reduces mechanotransduction in rat skeletal muscle afferents

Fukazawa, Ayumi; Hori, Amane; Hotta, Nigishi; Katanosaka, Kimiaki; Estrada, Juan A.; Ishizawa, Rie; Kim, Han-Kyul; Iwamoto, Gary A.; Smith, Scott A.; Vongpatanasin, Wanpen; Mizuno, Masaki

doi:10.1113/jp284026

Cited by 8 publications

(5 citation statements)

References 68 publications

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“…In addition to the itch regulation, TRPV4 also plays a significant role in modulating neuropathic pain 9,28 and mechanotransduction in muscle fiber afferents. 20 Moreover, TRPV4 exhibits widespread expression in brain neurons, serving as a potential risk factor for the development of brain diseases, 36 including cerebral ischemic reperfusion injury, 29 brain edema, 39 intracerebral hemorrhage, 52 epilepsy, 62 and Parkinson disease. 35 Thus, the function of TRPV4 in the body is broad, rather than itch specific.…”

Section: Discussionmentioning

confidence: 99%

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates

Xie,

Rao,

Tian

et al. 2024

Pain

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Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus.

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Section: Discussionmentioning

confidence: 99%

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates

Xie,

Rao,

Tian

et al. 2024

Pain

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“…The isoflurane concentration was 4% for induction and 1–1.5% for maintenance. A tail pinch was used to monitor anaesthesia depth consistently, and the absence of a withdrawal response confirmed adequate anaesthesia (Fukazawa et al., 2023). Hair on the neck was shaved using a clipper.…”

Section: Methodsmentioning

confidence: 99%

“…During electrode placement, male rats were anaesthetized with 4% isoflurane for induction and 1–1.5% for maintenance. Anaesthesia depth was checked with tail pinch and no response indicated adequate anaesthesia (Fukazawa et al., 2023). Hair on the temporal area was shaved using a clipper.…”

Section: Methodsmentioning

confidence: 99%

Cathodal bilateral transcranial direct‐current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia–reperfusion injury

Wang,

Ma,

et al. 2024

The Journal of Physiology

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Non‐invasive transcranial direct‐current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se‐dependent signalling in rat cerebral ischaemia–reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct‐current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen‐glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R‐insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R‐insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality‐control signalling, vesicle‐associated membrane protein 2 (VAMP2) and syntaxin‐4 (STX4), in OGD/R‐insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS‐ and BtDCS‐induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. imageKey points Cathodal bilateral transcranial direct‐current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra. Se plays a crucial role in cerebral ischaemia injury. Direct‐current stimulation reduces mitochondria injury and blocks the reduction of vesicle‐associated membrane protein 2 (VAMP2) and syntaxin‐4 (STX4) in oxygen‐glucose deprivation reoxygenation‐insulted neurons following coculturing with astrocytes. Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia.

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“…The receptor proteins on the afferents' endings that are stimulated by mechanical and metabolic stimuli have been investigated. So far, Piezo 2 and Transient Receptor Potential Vanilloid (TRPV) 4 channels have been shown to transduce mechanical stimuli (8,15). These mechanosensitive channels are believed to be located on the sensory endings of thinly myelinated group III muscle afferents.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone

Anselmi,

Ducrocq,

Kim

et al. 2024

Journal of Applied Physiology

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When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in dorsal ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This finding prompted us to determine if endomorphin 2 and oxycodone, infused into the arterial supply of freely perfused muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction. The endomorphin 2-induced potentiation of the pressor responses to contraction were prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control, 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion, and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion (n=10). Infusion of endomorphin and naloxone did not potentiate the pressor responses in ASIC3 knockout rats (n=6). Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level. The peak pressor response averaged 23.1 ± 8.6 mmHg for control, 33.2 ± 11 mmHg after naloxone and oxycodone were infused, and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused (n=9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by endomorphin 2 potentiated the exercise pressor reflex.

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Antagonism of TRPV4 channels partially reduces mechanotransduction in rat skeletal muscle afferents

Abstract: support-information-section).

Cited by 8 publications

References 68 publications

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates

Cathodal bilateral transcranial direct‐current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia–reperfusion injury

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone

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