Human glial cell line‑derived neurotrophic factor (GDNF) family receptor alpha 3 (GFR alpha ‑3, GDNF R‑ alpha 3) is an approximately 50 kDa plasma membrane glycoprotein that is one of four GDNF receptors, all of which are glycosylphosphoinositol (GPI)‑anchored, contain three conserved cysteine repeats, and promote survival of neurons (1 ‑ 4). It is synthesized as a 400 aa precursor with a 31 aa N‑terminal signal sequence, a 343 aa mature segment, and a C‑terminal GPI attachment signal sequence (3 ‑ 5). Human GFR alpha ‑3 shares 81 ‑ 84% aa sequence identity with mouse, rat, equine, bovine and canine GFR alpha ‑3. GFR alpha ‑3 is expressed in the central nervous system only during the earliest stages of neurogenesis, while later it is predominantly found in developing and adult nociceptive sensory neurons (2, 4 ‑ 8). It is expressed with the shared GDNF coreceptor, the Ret receptor tyrosine kinase, in the trigeminal ganglion, pituitary gland, thymus, lung, and duodenum (2, 4). Its ligand, the GDNF family ligand artemin, is primarily expressed by immature Schwann cells in the peripheral nervous system, and vascular smooth muscle cells, directing axonal projection of sympathetic neurons (6, 7). Artemin first binds GFR alpha ‑3, which recruits Ret, forming a signaling complex that is a pentamer containing one artemin, two GFR‑ alpha 3, and two Ret molecules (1, 6, 9). Signals from this complex are required for the development and survival of the superior cervical ganglion (SCG) neurons, and deletion of mouse GFR alpha ‑3 results in deficits in the SCG and inhibited development of intestinal Peyer’s patches (6, 7, 10, 11).
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