Structure‐Function Relationships of Endothelins, Sarafotoxins, and Their Receptor Subtypes

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Abstract
In brain synaptic membranes not extensively washed, (+)‐5‐[3H]methyl‐10,1 l‐dihydro‐5H‐dibenzo[a, d]‐cyclohepten‐5,10‐imine ([3H]MK‐801) binding was markedly inhibited in a concentration‐dependent manner (at concentrations above 1 μM) by several compounds having antagonistic activity at the Ca2+‐binding protein calmodulin. Scatchard analysis revealed that N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalenesulfonamide (W‐7) inhibited the binding through a significant decrease in the density of binding sites without affecting the affinity at 10 μM. In membranes extensively washed and treated with a low concentration of Triton X‐100, L‐glutamic acid (Glu) drastically accelerated the initial association rate of [3H]MK‐801 binding with glycine (Gly), almost doubling the initial association rate found in the presence of Glu alone. The addition of W‐7 invariably reduced the initial association rate observed in the presence of either Glu alone or both Glu and Gly, without significantly altering the dissociation rate of bound [3H]‐MK‐801, irrespective of the presence of the two stimulatory amino acids. The maximal potencies of Glu, Gly, and spermidine in potentiating the binding were all attenuated by W‐7. These results suggest that calmodulin antagonists may interfere with opening processes of an ion channel associated with an N‐methyl‐D‐aspartate‐sensitive subclass of excitatory amino acid receptors in rat brain.

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