Heparin Inhibits Melatonin Binding and Signal Transduction in Chick Brain

Abstract

The high-affinity receptor for melatonin is coupled to a pertussis toxin-sensitive, inhibitory guanine nucleotide regulatory protein, G_i, which mediates inhibition of adenylate cyclase activity in the chick and other species. Heparin has been found to uncouple α₂-adrenoceptors from a similar G_i;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]iodomela-tonin with high- and low-affinities of K_H = 20 pM and K_L = 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 right-ward shift of the agonist competition curve than heparin and converted all high-affinity sites to a low affinity of ∼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 G_i, with a consequent decrease in binding affinity and a loss of receptor-mediated signalling.

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“…Also, administration of heparin may have effects currently unknown to us. As an example, during the review process of this paper we have been informed by one of the reviewers that heparin has been shown to interfere with melatonin binding and signal transduction in chick brain [38]. This interaction has not yet been shown in rats, however the same effect maybe confounding our data.…”