cAMP and voltage modulate rat auditory mechanotransduction by decreasing the stiffness of gating springs

Mecca, Andrew A.; Caprara, Giusy A.; Peng, Anthony W.

doi:10.1073/pnas.2107567119

Cited by 6 publications

(3 citation statements)

References 53 publications

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“…The LPHN2-mediated auditory MET is more similar to the signalling mechanism for smell perception than to that for visual perception, which relies mainly on the Gt-mediated inhibition of constitutive cGMP levels in photoreceptor cells. Consistent with our findings, cAMP has been proposed to modulate the sensitivity of the MET in cochlear hair cells (Mecca et al, 2022). Notably, a loss-of-function mutation in adenylyl cyclase 1 (AC1) caused by the deletion of the C-terminal 82 amino acids is linked to hearing loss in humans (Santos-Cortez et al, 2014).…”

Section: Discussionsupporting

confidence: 92%

The force-sensing GPCR LPHN2 is indispensable for normal auditory function

Yang,

Wang,

Zhou

et al. 2023

Preprint

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Auditory perception enables acoustic experiences, including listening to melodious music and engaging in linguistic communication. Conversion of the force sensation into electrical signals via mechanoelectrical transduction (MET) in cochlear hair cells is the key step for auditory perception; however, the sound receptor for auditory perception at the molecular level is not clear. Here, we found that hair cell-specific deficiency of the G protein-coupled receptor LPHN2 in Pou4f3-CreER+/-Lphn2fl/fl mice or pharmacological blockade of CNG ion channels in mice severely impaired hearing. Importantly, sensation of force by LPHN2 not only increased intracellular cAMP and calcium levels but also elicited rapid membrane depolarization of cochlear hair cells via Gs-dependent CNGA3 coupling. Both LPHN2 and CNGA3 were expressed at the stereocilia and cuticular plates and associated with each other. Notably, hearing loss in LPHN2-deficient mice was almost fully reversed by re-expression of LPHN2-GAIN in cochlear hair cells. Therefore, we propose that LPHN2 acts as a direct sound sensor in cochlear hair cells by mediating MET through Gs and CNGA3 coupling. Furthermore, both GPCR members and ion channels modulated by second messengers might actively participate in the MET process during auditory perception.

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Section: Discussionsupporting

confidence: 92%

The force-sensing GPCR LPHN2 is indispensable for normal auditory function

Yang,

Wang,

Zhou

et al. 2023

Preprint

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“…Spatial confinement through inclusion in local signalosomes as a mechanism to secure specificity of response is not exclusive to PKA and has also been shown for other cAMP effectors, including the exchange factor directly activated by cAMP (EPAC) proteins (153)(154)(155)(156) and the Popeye domain-containing (POPDC) proteins (157,158). Given that these effectors modulate their own distinct cellular functions, they are also expected to be activated locally by confined pools of cAMP.…”

Section: Signaling By Camp Nanodomainsmentioning

confidence: 96%

G Protein–Coupled Receptor Signaling: New Insights Define Cellular Nanodomains

Lohse,

Bock,

Zaccolo

2024

Annu. Rev. Pharmacol. Toxicol.

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G protein–coupled receptors are the largest and pharmacologically most important receptor family and are involved in the regulation of most cell functions. Most of them reside exclusively at the cell surface, from where they signal via heterotrimeric G proteins to control the production of second messengers such as cAMP and IP3 as well as the activity of several ion channels. However, they may also internalize upon agonist stimulation or constitutively reside in various intracellular locations. Recent evidence indicates that their function differs depending on their precise cellular localization. This is because the signals they produce, notably cAMP and Ca2+, are mostly bound to cell proteins that significantly reduce their mobility, allowing the generation of steep concentration gradients. As a result, signals generated by the receptors remain confined to nanometer-sized domains. We propose that such nanometer-sized domains represent the basic signaling units in a cell and a new type of target for drug development. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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“…In response to magnetic stimulation, the tension force was produced by magnetic beads attached to the N-terminus of selected aGPCRs, and the activation of Gs or Gi signaling downstream of mechanosensitive GPCRs was measured by BRET signals. The Gs/Gi signal was selected as a readout because recent studies have indicated critical roles of Gi protein and cAMP levels in the regulation of stereocilium development, vestibular function and hair cell mechanotransduction [37][38][39] . Using this system, we revealed that 5 receptors (GPR133, GPR126, LPHN2, LPHN3 and VLGR1) activated Gi signaling in response to force stimulation, whereas 3 receptors (GPR133, LPHN2 and VLGR1) activated Gs signaling in response to force application (Figure 1D).…”

mentioning

confidence: 99%

Force sensing GPR133 is essential for normal balance and modulates vestibular hair cell membrane excitability via Gi signaling and CNGA3 coupling

Yang,

Zhou,

Wang

et al. 2023

Preprint

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The maintenance of normal balance sensing is a fundamental prerequisite for virtually every activity of daily life. As one set most important balance information collectors, vestibular hair cells convert mechanical stimuli from head movement into electrical signals through a mechanoelectrical transduction (MET) process. The molecular mechanism underlying equilibrioception and MET in vestibular hair cells is not well understood but is generally believed to be mediated by ion channels. However, whether these procedures are also mediated by other receptors, such as GPCRs, which are known to govern light, odorant and taste sensing, is not known. Here, by screening the expression of force-sensitive adhesion GPCRs in vestibular hair cells and phenotype profiling in animal models, we identified that a seven-transmembrane receptor, GPR133, was able to sense force in utricle hair cells and was required for maintenance of normal equilibrioception. Notably, GPR133 converted mechanical stimuli into changes in intracellular cAMP levels through Gi engagement and then modulated plasma membrane excitability and mediated MET by coupling to CNGA3 activity changes in approximately 30% of GPR133-expressing utricle hair cells. GPR133-mediated MET and its coupling with CNGA3 were recapitulated by an in vitro reconstitution system. Further chemical labeling, mass spectrometry and cryo-EM analysis provided potential structural information on force-induced GPR133 activation and Gi3 engagement. Collectively, our findings reveal the essential role of GPR133 in the maintenance of normal equilibrioception and suggest that GPCR family members can participate in the MET process in utricle hair cells through modulation of intracellular second messenger levels and ion channel coupling.

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cAMP and voltage modulate rat auditory mechanotransduction by decreasing the stiffness of gating springs

Cited by 6 publications

References 53 publications

The force-sensing GPCR LPHN2 is indispensable for normal auditory function

The force-sensing GPCR LPHN2 is indispensable for normal auditory function

G Protein–Coupled Receptor Signaling: New Insights Define Cellular Nanodomains

Force sensing GPR133 is essential for normal balance and modulates vestibular hair cell membrane excitability via Gi signaling and CNGA3 coupling

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