Artemin, a Novel Member of the GDNF Ligand Family, Supports Peripheral and Central Neurons and Signals through the GFRα3–RET Receptor Complex

Abstract

The glial cell line-derived neurotrophic factor (GDNF) ligands (GDNF, Neurturin [NTN], and Persephin [PSP]) signal through a multicomponent receptor system composed of a high-affinity binding component (GFRalpha1-GFRalpha4) and a common signaling component (RET). Here, we report the identification of Artemin, a novel member of the GDNF family, and demonstrate that it is the ligand for the former orphan receptor GFRalpha3-RET. Artemin is a survival factor for sensory and sympathetic neurons in culture, and its expression pattern suggests that it also influences these neurons in vivo. Artemin can also activate the GFRalpha1-RET complex and supports the survival of dopaminergic midbrain neurons in culture, indicating that like GDNF (GFRalpha1-RET) and NTN (GFRalpha2-RET), Artemin has a preferred receptor (GFRalpha3-RET) but that alternative receptor interactions also occur.

Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

“…With this in mind, we examined trophic support in the aged ganglia by measuring the relative expression of receptors that bind the GDNF family of ligands, with particular interest in the GPI-anchored GFRα3 receptor. Neurons that express GFRα3, which binds the growth factor artemin, comprise approximately 20% of the lumbar mouse DRG population, show 99% colocalization with TRPV1 [31] and express the tyrosine kinase Ret [3]. Results show the relative abundance of GFRα3 is decreased in aged ganglia on both the transcriptional and translational level in lumbar DRG suggesting this TRPV1 enriched population is preferentially affected in aging systems.…”

Neurotrophic Artemin Promotes Motility and Invasiveness of MIA PaCa-2 Pancreatic Cancer Cells

“…As shown in the literature, in adult and fetal mice, Artemin expression is present in the nervous system, concentrated in DRG, immature Schwann cells, and weakly in the brain (Baloh et al, 1998). Under physiologic conditions, Artemin is localized in vascular smooth muscle cells, in the adventitia of the dorsal aorta and arteries entering the gut (Baloh et al, 1998;Enomoto et al, 2001;Honma et al, 2002). In the normal pancreas, Artemin was faintly present in smooth muscle cells of arteries but absent in intrapancreatic nerves or ducts.…”

“…Artemin with its receptor complex (GFRα3/RET) tend to form a ligand/receptor complex by glycosyl-phosphatidylinositol (GPI) anchored in the cell membrane, activation of Ret, which pass signals. As shown in the literature, in adult and fetal mice, Artemin expression is present in the nervous system, concentrated in DRG, immature Schwann cells, and weakly in the brain (Baloh et al, 1998). Under physiologic conditions, Artemin is localized in vascular smooth muscle cells, in the adventitia of the dorsal aorta and arteries entering the gut (Baloh et al, 1998;Enomoto et al, 2001;Honma et al, 2002).…”

“…Artemin widely expressed in various tumor tissues, involved in tumor development. Andres et al (Andres et al, 2001) and Baloh et al (Baloh et al, 1998;Andres et al, 2001) demonstrated the increase of neuroblastoma cell proliferation induced by Artemin. Ceyhan et al have found that Artemin and GFRα3/RET receptors were overexpressed in PDAC compared with the normal pancreas, and has a significant role in promoting proliferation and nerve infiltration, however, this effect was not observed in PAC cell lines (Ceyhan et al, 2006).…”

Neurotrophic factors for the treatment of Parkinson's disease

“…This factor also has trophic effects on motor neurones [96] and has not been extensively investigated for its clinical potential in PD. The fourth member of the GFL family, artemin, has survivalpromoting effects on dopaminergic neurones in culture [98] and in vivo [99], and also has potent actions on sensory neurones of the dorsal root ganglia [98]. Like persephin, artemin has not progressed into clinical trials for PD; however it has been tested as a therapeutic for neuropathy [100].…”