Regulation of TRPM2 channels in neutrophil granulocytes by ADP-ribose: a promising pharmacological target.
TRPM2 channels play an important role in the activation process of neutrophil granulocytes. One mechanism of TRPM2 channel gating is the binding of intracellular ADP ribose (ADPR) to the Nudix box domain in the C-terminal tail of TRPM2. Intracellular Ca(2+), although not an activator of TRPM2 by its own, significantly enhances TRPM2 gating by ADPR. Stimulation of neutrophil granulocytes with the chemoattractant peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) induces release of Ca(2+) ions from intracellular stores which in cooperation with endogenous ADPR levels enable Ca(2+) influx through TRPM2. Stimulation of the ectoenzyme CD38, a membrane-associated glycohydrolase with ADPR as main product, and uptake of ADPR into the cell may contribute to the effects of fMLP. Inhibition of ADPR production, of uptake and of binding to TRPM2 are all potential pharmacological principles by which a modulation of neutrophil function may become possible in future.
Heiner
Inka
I
Institut für Physiologie, Medizinische Fakultät der Rheinisch-Westfälischen Technischen Hochschule, 52057, Aachen, Germany.
Radukina
Natalia
N
Eisfeld
Jörg
J
Kühn
Frank
F
Lückhoff
Andreas
A
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D000246:Adenosine Diphosphate Ribose; D002118:Calcium