Abstract
Artemin (ARTN) is a neurotrophic factor from the GDNF family ligands (GFLs) that is involved in development of the nervous system and neuronal differentiation and survival. ARTN signals through a complex receptor system consisting of the RET receptor tyrosine kinase and a glycosylphosphatidylinositol-anchored co-receptor GFL receptor α, GFRα3. We found that ARTN binds directly to neural cell adhesion molecule (NCAM) and that ARTN-induced neuritogenesis requires NCAM expression and activation of NCAM-associated signaling partners, thus corroborating that NCAM is an alternative receptor for ARTN. We designed a small peptide, artefin, that could interact with GFRα3 and demonstrated that this peptide agonist induces RET phosphorylation and mimics the biological functions of ARTN – neuroprotection and neurite outgrowth. Moreover, artefin mimicked the binding of ARTN to NCAM and required NCAM expression and activation for its neurite elongation effect, thereby suggesting that artefin represents a binding site for NCAM within ARTN. We showed that biological effects of ARTN and artefin can be inhibited by abrogation of both NCAM and RET, suggesting a more complex signaling mechanism that previously thought. As NCAM plays a significant role in neurodevelopment, regeneration, and synaptic plasticity we suggest that ARTN and its mimetics are promising candidates for treatment of neurological disorders and warrant further investigations.
Highlights
Neurotrophic factors play an essential role in the survival, differentiation, and maintenance of neurons in the central and peripheral nervous systems (Anders et al, 2001; Enomoto et al, 2001; Honma et al, 2002)
We found that ARTN bound directly to neural cell adhesion molecule (NCAM), and that both NCAM expression and activation of downstream signaling partners were required for ARTN-induced neurite outgrowth, thereby indicating that NCAM is an alternative receptor for ARTN
We focused on the α-helical heel region of ARTN, where a number of side chains are exposed outside of the dimer and available for potential interactions with other molecules
Summary
Neurotrophic factors play an essential role in the survival, differentiation, and maintenance of neurons in the central and peripheral nervous systems (Anders et al, 2001; Enomoto et al, 2001; Honma et al, 2002). Their discovery and characterization have been instrumental for the understanding of the development, plasticity, and repair of the nervous system (Baloh et al, 2000a). Artemin (ARTN) is a member of the glial cell line-derived neurotrophic factor family ligands (GFLs) which includes three other members: glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), and persephin (PSPN) (Baloh et al, 1998b; Airaksinen and Saarma, 2002). ARTN plasma levels are reduced in patients with major depressive disorder (Pallanti et al, 2014), and intracerebroventricular administration of ARTN shows dose-dependent antidepressant effects in mice, potentially via modulation of neuronal plasticity (Mannelli et al, 2011)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
