Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin2 G protein–coupled receptor

Babin, Katie M; Karim, Jordan A.; Gordon, Peyton H; Lennon, James; Dickson, Alex; Pioszak, Augen A.

doi:10.1016/j.jbc.2023.104785

Cited by 4 publications

(1 citation statement)

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“…Additionally, AREG and STC2 were also upregulated in response to MPC inhibition. The protein products of these genes could collectively have important physiological effects [61][62][63] on the hair follicle as stress-responsive secretory factors. Furthermore, our study identified other potentially important genes for hair growth and immune regulation.…”

Section: Differential Expression Of Stress-responsive Genes In Hair F...mentioning

confidence: 99%

Activation of the integrated stress response in human hair follicles

Pye,

Scholey,

Ung

et al. 2024

PLoS ONE

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Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and provide new targets to manage hair loss disorders. The Mitochondrial Pyruvate Carrier (MPC) imports pyruvate, produced via glycolysis, into the mitochondria, fuelling the TCA cycle. Previous work has shown that MPC inhibition promotes lactate generation, which activates murine epithelial hair follicle stem cells (eHFSCs). However, by pharmacologically targeting the MPC in short-term human hair follicle ex vivo organ culture experiments using UK-5099, we induced metabolic stress-responsive proliferative arrest throughout the human hair follicle epithelium, including within Keratin 15+ eHFSCs. Through transcriptomics, MPC inhibition was shown to promote a gene expression signature indicative of disrupted FGF, IGF, TGFβ and WNT signalling, mitochondrial dysfunction, and activation of the integrated stress response (ISR), which can arrest cell cycle progression. The ISR, mediated by the transcription factor ATF4, is activated by stressors including amino acid deprivation and ER stress, consistent with MPC inhibition within our model. Using RNAScope, we confirmed the upregulation of both ATF4 and the highly upregulated ATF4-target gene ADM2 on human hair follicle tissue sections in situ. Moreover, treatment with the ISR inhibitor ISRIB attenuated both the upregulation of ADM2 and the proliferative block imposed via MPC inhibition. Together, this work reveals how the human hair follicle, as a complex and metabolically active human tissue system, can dynamically adapt to metabolic stress.

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Section: Differential Expression Of Stress-responsive Genes In Hair F...mentioning

confidence: 99%