Oi:ten.1530 JME-15-0268 9. Chretien M, Mbikay M. 60 years of POMC: in the prohormone theory to proopiomelanocortin and to proprotein convertases (PCSK1 to PCSK9). J Mol Endocrinol (2016) 56(4):T492. doi:10.1530JME-15-Review published: 17 November 2017 doi: ten.3389fendo.2017.New insights in to the Mechanism of Action of Soluble KlothoGeorge D. Dalton1, Jian Xie2, Sung-Wan An two and Chou-Long Huang21Department of Bentiromide Epigenetics Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, United states of america, Department of Internal Medicine, Division of Nephrology and Hypertension, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesEdited by: Reinhold Gottfried Erben, Veterin medizinische Universit Wien, Austria Reviewed by: Chrishan S. Samuel, Division of Pharmacology, Monash University, Australia Guillermo Romero, University of Pittsburgh, Usa Correspondence: Chou-Long Huang [email protected] Specialty section: This short article was submitted to Molecular and Structural Endocrinology, a section with the journal Frontiers in Endocrinology Received: 01 August 2017 Accepted: 02 November 2017 Published: 17 November 2017 Citation: Dalton GD, Xie J, An S-W and Huang C-L (2017) New Insights into the Mechanism of Action of Soluble Klotho. Front. Endocrinol. 8:323. doi: 10.3389fendo.2017.The klotho gene encodes a variety I single-pass transmembrane protein that consists of a sizable extracellular domain, a membrane spanning segment, plus a brief intracellular domain. Klotho protein exists in numerous forms which includes the full-length membrane kind (mKl) as well as a soluble circulating type [soluble klotho (sKl)]. mKl complexes with fibroblast development element receptors to type coreceptors for FGF23, which enables it to take part in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present within the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channelstransporters and development aspect signaling. How sKl exerts these pleiotropic functions is poorly understood. One particular hurdle in understanding sKl’s mechanism of action as a “hormone” has been the inability to recognize a receptor that mediates its effects. Within the physique, the kidneys are a significant supply of sKl and sKl levels decline for the duration of renal disease. sKl deficiency in chronic kidney disease tends to make the heart susceptible to stress-induced injury. Here, we summarize the current know-how of mKl’s mechanism of action, the mechanistic basis of sKl’s protective, FGF23-independent effects on the heart, and present new insights into the mechanism of action of sKl focusing on current findings that sKl binds sialogangliosides in membrane lipid rafts to regulate development element signaling.Keywords and phrases: klotho, FGF23, lipid rafts, aging, TRPC6, sialidase, iGF-1, heart diseaseDiSCOveRY In the AGiNG-SUPPReSSOR GeNe klothoFor decades, scientists have searched for genes that regulate lifespan. In 1997, one particular such gene was identified within a transgenic mouse strain whose mutation resulted in a syndrome resembling premature aging that incorporated shortened lifespan, growth retardation, vascular calcification, genital atrophy, emphysema, and osteomalacia (1). The gene was named klotho, which in Greek mythology is one of the three goddesses of fate who spins the thread of life (1). The aging phenotypes had been observed exclusively in mice that have been homozygous for SLC9A1 transgene insertion in to the 5 flanking region in the k.