GFRα4
GFRα3 is a GPI-linked GDNF-family co-receptor that binds artemin and forms a signaling complex with RET to support sensory and sympathetic neurons[1]. Mechanistically, the ARTN-GFRα3 complex initiates formation of a ternary receptor complex containing shared RET, linking ligand recognition to downstream neurotrophic signaling[2]. In sensory biology, GFRα3 marks nociceptive dorsal root ganglion neurons that coexpress RET, TRPV1, TrkA, peripherin, and CGRP, distinguishing an artemin-responsive nociceptor subset from the GDNF-responsive population[3]. Artemin and other GDNF-family ligands sensitize thermal nociceptors, while artemin shows particular relevance to inflammatory hyperalgesia[4]. In pain models, GFRα3 is required for inflammatory and neuropathic cold allodynia, and artemin-GFRα3 signaling acts through TRPM8-dependent cold-pain mechanisms[5][6]. Compared with related isoforms, GFRα3 differs from GFRα1 because GFRα1 is highly selective for GDNF rather than artemin[7]. For experimental applications, anti-GFRα3 monoclonal antibodies reduced evoked allodynia and thermal hyperalgesia in mouse joint-pain models, but REGN5069 did not improve knee osteoarthritis pain in a phase 2 trial[8].
Références:
- [1]. Baloh RH, et al. Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. Neuron. 1998 Dec;21(6):1291-302. [Content Brief]
- [2]. Wang X, et al. Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors. Structure. 2006 Jun;14(6):1083-92. [Content Brief]
- [3]. Orozco OE, et al. GFRalpha3 is expressed predominantly in nociceptive sensory neurons. Eur J Neurosci. 2001 Jun;13(11):2177-82. [Content Brief]
- [4]. Malin SA, et al. Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci. 2006 Aug 16;26(33):8588-99. [Content Brief]
- [5]. Lippoldt EK, et al. Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4506-11. [Content Brief]
- [6]. Lippoldt EK, et al. Artemin, a glial cell line-derived neurotrophic factor family member, induces TRPM8-dependent cold pain. J Neurosci. 2013 Jul 24;33(30):12543-52. [Content Brief]
- [7]. Carmillo P, et al. Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-1 (GFR alpha 1) is highly selective for GDNF versus artemin. Biochemistry. 2005 Feb 22;44(7):2545-54. [Content Brief]
- [8]. Somersan-Karakaya S, et al. Monoclonal antibodies against GFRα3 are efficacious against evoked hyperalgesic and allodynic responses in mouse join pain models but, one of these, REGN5069, was not effective against pain in a randomized, placebo-controlled clinical trial in patients with osteoarthritis pain. Neurobiol Pain. 2023 Jun 26;14:100136. [Content Brief]
