Abstract
α-Klotho is a type 1 transmembrane protein that exhibits aging suppression function. The large amino-terminal extracellular domain of α-klotho is shed as soluble klotho (sKlotho) and functions as a circulating cardioprotective hormone. Diacylglycerol (DAG)-activated calcium-permeable TRPC6 channel plays a critical role in stress-induced cardiac remodeling. DAG activates TRPC6 by acting directly on the channel to increase its activity and by stimulation of channel exocytosis. sKlotho protects the heart by inhibiting DAG stimulation of TRPC6 exocytosis. How DAG stimulates TRPC6 exocytosis and thereby inhibition by sKlotho are unknown. Using a compound that directly activates TRPC6 without affecting channel exocytosis, we validate that sKlotho selectively blocks DAG stimulation of channel exocytosis. We further show that DAG stimulates exocytosis of TRPC6-containing vesicles pre-docked to the plasma membrane. Mnuc13 family proteins play important roles in the proper assembly of SNARE proteins and priming the vesicle competent for fusion. We show that DAG stimulates TRPC6 exocytosis by targeting to the C1 domain of Munc13-2. The results provide fresh insights into the molecular mechanism by which DAG regulates vesicle fusion and how sKlotho protects the heart against injury.
Highlights
Introduction αKlotho is a type 1 transmembrane protein predominantly produced in the kidney, choroid plexuses of the brain, parathyroid gland, and to a lesser extend in several other tissues [1]
We have shown that soluble klotho (sKlotho) protects against stress-induced cardiac hypertrophy by inhibiting growth factor-stimulated phosphoinositide 3-kinase (PI3K)-dependent exocytosis of TRPC6 channels [14, 15]
We found that sKlotho and exocytosis blocker tetanus toxin (TTX) each partially blocks DAG-stimulated TRPC6 current and that their effects are not additive [14, 15]
Summary
Klotho is a type 1 transmembrane protein predominantly produced in the kidney, choroid plexuses of the brain, parathyroid gland, and to a lesser extend in several other tissues [1]. Mice homozygous for hypomorphic klotho allele (kl/kl) exhibit phenotypes resembling premature human aging [1]. Overexpression of α-klotho transgene in mice results in extended lifespan [2]. Single nucleotide polymorphisms have been identified in the klotho gene that correlate with reduced longevity and the pathophysiology of age-related disorders such as osteoporosis, coronary artery disease, and stroke [3,4,5,6]. Membranous α-klotho associates with fibroblast growth factor (FGF) receptors to form coreceptors for the ligand FGF23 [7, 8]. Α-Klotho-deficient mice have severe hyperphosphatemia due to defects in the klotho-FGF23-vitamin D FGF23 is a bone-derived circulating hormone that lowers serum phosphate levels by increasing renal phosphate excretion, suppressing 1,25-dihyroxyvitamin D synthesis, and decreasing gastrointestinal phosphate absorption [9]. α-Klotho-deficient mice have severe hyperphosphatemia due to defects in the klotho-FGF23-vitamin D
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
