1. CCK-8 stimulation of ventromedial hypothalamic neurons in vitro: a feeding-relevant event?
D W Pfaff, L M Kow Peptides . 1986 May-Jun;7(3):473-9. doi: 10.1016/0196-9781(86)90017-3.
Bath application of sulfated or non-sulfated cholecystokinin octapeptide (CCK-8s or CCK-8ns, respectively) at concentrations of 25 to 250 nM stimulated the firing activity of 40 to 80% of neurons recorded from the ventromedial nucleus (VMN) in hypothalamic slices maintained in vitro. On the basis of molarity or the percentages of neurons affected, CCK-8s was about 2 to 10 times more potent than CCK-8ns. However, qualitatively, the two forms of CCK-8 were virtually identical: both had a stimulatory action on VMN neurons; both affected VMN neurons in a dose-dependent fashion; both could desensitize their own stimulatory action; and both could cross-desensitize the stimulatory action of the other. These results indicate that not only CCK-8s but also CCK-8ns, which is biologically inactive peripherally, can serve as excitatory neurotransmitters in the VMN, and that both peptides stimulated neurons through the same or a similar neuronal mechanism. It was also found that in the VMN, the stimulatory action of CCK-8 correlated with the actions of norepinephrine, and affected all of the VMN neurons responsive to glucose. Since the actions of glucose and norepinephrine on the activity of VMN neurons are feeding-relevant, our data support the notion that, in addition to acting as a peripheral satiety agent, CCK-8 can also act as a neurotransmitter centrally to mediate satiety.
2. 3'-Phosphoadenosine 5'-phosphosulfate biosynthesis and the sulfation of cholecystokinin by the tyrosylprotein-sulfotransferase in rat brain tissue
O Frerot, M D Trung Tuong, C Gulat-Marnay, A Lafitte, F Vargas, F Brion Chem Biol Interact . 1994 Jun;92(1-3):281-91. doi: 10.1016/0009-2797(94)90070-1.
This article resumes the work we have accomplished in the past few years. Cholecystokinin sulfation is an important post-translational modification necessary for the biological activity of this peptide hormone. The tyrosyl protein sulfotransferase (TPST) activity from rat cerebral cortex was characterized. TPST activity is most probably responsible for the endogenous sulfation of CCK. TPST reaction kinetic properties were studied using radiolabeled 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and the non-sulfated peptide acceptor terbutyloxycarbonyl-cholecystokinin octapeptide (BocCCK-8(ns)) as substrates, and brain microsomes as the enzyme source. The BocCCK-8 sulfating reaction data is consistent with the idea that TPST forward reaction follows an ordered Bi Bi mechanism. PAPS biosynthesis and availability was studied in slices from rat cerebral cortex incubated in the presence of [35S]sulfate. There is a rapid and dynamic turnover of the steady-state level of PAPS in brain cells which is decreased by depolarizing agents such as potassium, veratridine and glutamate. Furthermore, the presence of a membrane-bound PAPS biosynthesis inhibitor was observed. These results are discussed in view of the biological importance that the cell sulfating pathways might play in nerve cell activity.
3. The effects of cholecystokinin and cholecystokinin antagonists on synaptic function in the CA1 region of the rat hippocampal slice
P G Aitken, J V Nadler, D B Jaffe Brain Res . 1987 Jul 7;415(1):197-203. doi: 10.1016/0006-8993(87)90288-5.
The effects of two CCK antagonists, benzotript and proglumide, and of sulfated and non-sulfated cholecystokinin octapeptide (CCK-8-S and CCK-8-NS), were studied in the CA1 region of the rat hippocampal slice. Both benzotript and proglumide shifted presynaptic volley (prevolley) vs population spike input/output (I/O) curves for Schaffer collateral-commissural synaptic transmission to the right. This result indicates that the antagonists had a net depressant effect on synaptic transmission. CCK-8-S shifted prevolley vs population spike I/O curves to the left, indicating a net excitatory effect. Analysis of component I/O curves indicated that CCK-8-S and the CCK antagonists were acting postsynaptically by changing CA1 pyramidal cell threshold. CCK-8-NS had no significant effect on overall or component I/O functions. These findings suggest that endogenous CCK is released, directly or indirectly, upon stimulation of the Schaffer collateral-commissural fibers and increases the excitability of CA1 pyramidal cells.
