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D. Sugden


2-Iodomelatonin, a ligand which has recently been used to identify melatonin-binding sites in the brain, produced condensation of pigment granules when added to isolated Xenopus laevis melanophores in culture. Melatonin (EC 50 = 5.7 × 10−13 mol/l), 2-iodomelatonin (EC 50 = 3.4 × 10−12 mol/l) and also 2-chloromelatonin (EC 50 = 2.9 × 10−13 mol/l) were all potent agonists in this test. Melatonin analogues in which the side-chain was conformationally restricted by linkage to the 2-position of the indole ring were inactive (EC 50 > 10−6 mol/l). The remarkable sensitivity and selectivity of this pigment condensation response suggests it will be useful in future studies of melatonin agonists and antagonists.

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HT Al-Majed, PM Jones, SJ Persaud, D Sugden, GC Huang, S Amiel, and BJ Whitehouse

It has previously been suggested that ACTH and ACTH-related peptides may act as paracrine modulators of insulin secretion in the islets of Langerhans. We have, therefore, examined the expression and function of the ACTH receptor (the melanocortin 2 receptor, MC2-R) in human and mouse primary islet tIssue and in the MIN6 mouse insulinoma cell line. Mouse MC2-R mRNA was detected in both MIN6 cells and mouse islet tIssue by PCR amplification of cDNA. In perifusion experiments with MIN6 pseudo-islets, a small, transient increase in insulin secretion was obtained when ACTH(1-24) (1 nM) was added to medium containing 2 mM glucose (control) but not when the medium glucose content was increased to 8 mM. Further investigations were performed using static incubations of MIN6 cell monolayers; ACTH(1-24) (1 pM-10 nM) provoked a concentration-dependent increase in insulin secretion from MIN6 monolayer cells that achieved statistical significance at concentrations of 1 and 10 nM (150 +/- 13.6% basal secretion; 187 +/- 14.9% basal secretion, P<0.01). Similar responses were obtained with ACTH(1-39). The phosphodiesterase inhibitor IBMX (100 microM) potentiated the responses to sub-maximal doses of ACTH(1-24). Two inhibitors of the protein kinase A (PKA) signaling pathway, Rp-cAMPS (500 microM) and H-89 (10 microM), abolished the insulin secretory response to ACTH(1-24) (0.5-10 nM). Treatment with 1 nM ACTH(1-24) caused a small, statistically significant increase in intracellular cAMP levels. Secretory responses of MIN6 cells to ACTH(1-24) were also influenced by changes in extracellular Ca2+ levels. Incubation in Ca2+-free buffer supplemented with 0.1 mM EGTA blocked the MIN6 cells' secretory response to 1 and 10 nM ACTH(1-24). Similar results were obtained when a Ca2+ channel blocker (nitrendipine, 10 microM) was added to the Ca2+-containing buffer. ACTH(1-24) also evoked an insulin secretory response from primary tIssues. The addition of ACTH(1-24) (0.5 nM) to perifusions of mouse islets induced a transient increase in insulin secretion at 8 mM glucose. Perifused human primary islets also showed a secretory response to ACTH(1-24) at basal glucose concentration (2 mM) with a rapid initial spike in insulin secretion followed by a decline to basal levels. Overall the results demonstrate that the MC2-R is expressed in beta-cells and suggest that activation of the receptor by ACTH initiates insulin secretion through the activation of PKA in association with Ca2+ influx into beta-cells.

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E. C. Osborn, P. L. Sugden, J. C. Mackenzie, D. M. Aitken, I. D. Chapman, S. Howes, O. F. Mason, G. V. Rigby, and J. Wilson


Angiotensin II and I significantly raised potassium and lowered sodium and chloride ion concentrations in arterial plasma, with peak changes occurring in the first 2 min of a 6-min infusion period. The octapeptide increased the arterial K+ level in a dose-dependent manner, but the response showed tachyphylaxis when multiple infusions of 6-min duration were administered after a recovery interval of only 5 min. Raising the arterial blood pressure by 20–33 mmHg with adrenaline and noradrenaline failed to account for the increase in arterial plasma K+ concentration produced by the two peptides. These findings, in particular the rise in K+ concentration, are discussed in relation to possible mechanisms by which angiotensin II affects arteriolar tone.

J. Endocr. (1985) 104, 143–148