The primary mechanism of activation of intracellular prohormones seems to involve proteolytic cleavage at sequences of consecutive basic residues. Thus, all the known biologically active peptides derived from the prohormone of corticotropin and beta-endorphin appear to be excised initially by enzymes with this specificity. The C-terminal peptide, beta-endorphin (1-31), is generated by cleavage at a lysyl arginine sequence and an additional cleavage can give rise to the related peptides, beta-endorphin (1-27) and beta-endorphin (1-26). These derivatives of beta-endorphin are released by an endopeptidase that appears to catalyse cleavage on the carboxyl side of paired lysine residues, followed by the action of a carboxypeptidase B-like enzyme (Fig. 1). The beta-endorphin fragments, beta-endorphin (1-27) and beta-endorphin (1-26), have been isolated from porcine and bovine pituitary but the C-terminal dipeptide, glycyl glutamine, has not been reported previously. Here we describe the isolation of glycyl glutamine from porcine pituitary and present evidence for its presence in sheep brain stem. When applied ionophoretically to brain stem neurones in the rat, the dipeptide exhibited an inhibitory action on cell firing.
1 The effects of microiontophoretically applied methionyl-tyrosyl-lysine (Met-Tyr-Lys) were studied on single neurones in several brain regions of rats anaesthetized with urethane. 2 Met-Tyr-Lys inhibited 13.5%-25% of neurones in the spinal cord, cerebellar cortex, thalamus and hippocampal formation. No significant inhibitory effects were seen in the cerebral cortex. 3 Additionally, Met-Tyr-Lys excited some cells in the Purkinje cell body layer of the cerebellar cortex (11 %) and in the pyramidal cell body layer of the hippocampus and granule cell body layer of the dentate gyrus within the hippocampal formation (17.5%). 4 Both excitatory and inhibitory effects of Met-Tyr-Lys were dose-dependent, of similar rapid time course and were observed both on spontaneously active cells and cells induced to fire by continuous iontophoretic application of DL-homocysteic acid. 5 The possibility that Met-Tyr-Lys might be a novel inhibitory neurotransmitter in both spinal and supraspinal regions of the mammalian CNS is discussed.
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