Heparin inhibits melatonin binding and signal transduction in chick brain.
The high-affinity receptor for melatonin is coupled to a pertussis toxin-sensitive, inhibitory guanine nucleotide regulatory protein, Gi, which mediates inhibition of adenylate cyclase activity in the chick and other species. Heparin has been found to uncouple alpha 2-adrenoceptors from a similar Gi; therefore it was of interest to examine the effect of this agent on melatonin binding and signal transduction in chick brain. In competition studies, melatonin inhibited the binding of 2-[125I]iodo-melatonin with high- and low-affinities of KH = 20 pM and KL = 15 nM, respectively. In the presence of heparin (100 units/ml), a single site with an affinity of about 6 nM was detected. The monovalent cations, Na+ and Li+, produced a greater rightward shift of the agonist competition curve than heparin and converted all high-affinity sites to a low affinity of approximately 15-18 nM. In saturation studies, heparin reduced the affinity of high-affinity sites and caused a significant decrease in the density of low-affinity sites. In keeping with its ability to reduce high-affinity binding, heparin blocked melatonin's inhibitory effect on forskolin-stimulated adenylate cyclase activity in chick brain synaptosomal membranes. These findings indicate that heparin impairs the coupling between the melatonin receptor and Gi, with a consequent decrease in binding affinity and a loss of receptor-mediated signalling.
Niles
L P
LP
Department of Biomedical Sciences, McMaster University, Hamilton, Canada.
Harjivan
C
C
Nanji
A
A
D000818:Animals; D002645:Chickens; D006493:Heparin / Q000494:pharmacology*; D008094:Lithium / Q000494:pharmacology; D008550:Melatonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000378:metabolism
D006493:Heparin; D008094:Lithium; D008550:Melatonin