A role for NAD+ and cADP-ribose in melatonin signal transduction.
The hormone melatonin modulates constitutive protein secretion and inhibits cGMP in melanoma M2R cells via cholera-toxin (CTX) sensitive pathways. Activation by melatonin of CTX-substrates is due to enhancement of their ADP ribosylation. The possibility that ADP ribosylation was enhanced by elevation of NAD+ was studied. Melatonin enhanced NAD+ and decreased cADP-ribose in the cells, in a CTX independent pathway, indicating inhibition of nicotinamide adenine dinucleotide glycohydrolase (NADase). Dibutyryl cGMP (db-cGMP), which obviates the melatonin-induced decrease in cGMP and prevents the modulation of protein secretion, abrogated the enhancement of NAD+. cADP-ribose is involved in calcium homeostasis and its decrease may reduce intracellular Ca2+. The intracellular Ca2+ chelator BAPTA/AM mimicked and Ca2+ ionophores prevented the melatonin-induced inhibition of protein secretion. These data indicate for the first time hormonal modulation of NADase resulting in two signals: (1) enhancement of NAD+ which may explain the increase in ADP ribosylation and activation of CTX substrates leading to facilitation of protein secretion; (2) suppression of cell cADP-ribose and consequently intracellular Ca2+ which may explain the melatonin-induced inhibition of protein secretion.
Bubis
M
M
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
Zisapel
N
N
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D036563:Cyclic ADP-Ribose; D006801:Humans; D008545:Melanoma; D008550:Melatonin / Q000502:physiology*; D009243:NAD / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D009243:NAD; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D008550:Melatonin