cADP-ribose/ryanodine channel/Ca2+-release signal transduction pathway in mesangial cells.
Signaling via release of Ca2+ from intracellular stores is mediated by several systems, including the inositol 1,4,5-trisphosphate (IP3) and cADP-ribose (cADPR) pathway. We recently discovered a high capacity for cADPR synthesis in rat glomeruli and cultured mesangial cells (MC). We sought to determine whether 1) cADPR synthesis in MC is regulated by cytokines and hormones, 2) ryanodine receptors (RyRs) are expressed in MC, and 3) Ca2+ is released through RyRs in response to cADPR. We found that ADP-ribosyl cyclase, a CD38-like enzyme that catalyzes cADPR synthesis, is upregulated in MC by tumor necrosis factor-alpha, interleukin-1beta, and all-trans retinoic acid (atRA). [3H]ryanodine binds to microsomal fractions from MC with high affinity in a Ca2+-dependent manner; binding is enhanced by specific RyR agonists and blocked by ruthenium red and cADPR. Western blot analysis confirmed the presence of RyR in MC. Release of 45Ca2+ from MC microsomes was stimulated by cADPR; release was blocked by ruthenium red and 8-bromo-cADPR. ADPR (non-cyclic) was without effect. In MC, TNF-alpha and atRA amplified the increment of cytoplasmic Ca2+ elicited by vasopressin. We conclude that MC possess elements of a novel ADP-ribosyl cyclase-->cADPR-->RyR-->Ca2+-release signaling pathway subject to regulation by proinflammatory cytokines and steroid superfamily hormones.
Yusufi
A N
AN
Renal Pathophysiology Laboratory, Department of Physiology and Biophysics, Mayo Clinic, Mayo Medical School, Rochester, Minnesota 55905, USA.
Cheng
J
J
Thompson
M A
MA
Dousa
T P
TP
Warner
G M
GM
Walker
H J
HJ
Grande
J P
JP
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D014667:Vasopressins / Q000494:pharmacology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D002413:Cations, Divalent; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019837:Ryanodine Receptor Calcium Release Channel; D014409:Tumor Necrosis Factor-alpha; D014284:Triiodothyronine; D014667:Vasopressins; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D014212:Tretinoin; D036541:ADP-ribosyl Cyclase; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium