In vivo sulfation of cholecystokinin octapeptide. Possible interactions of the two forms of cholecystokinin with dopamine in the brain.
In most laboratories CCK-8(s) has been found to be the biologically active form of CCK-8 in the CNS. The role of CCK-8(ns) has scarcely been investigated and is poorly understood. CCK-8(s) exerts a transmitter and/or modulator role in this projection. CCK-8(ns), on the other hand, profoundly affects DA-ergic neurotransmission in the nigrostriatal DA-ergic projection. The octapeptide modulates the turnover and release of DA from this neuron population. DA-mediated behavioral reactions are also modulated by CCK-8(ns). We should emphasize that the biological importance of CCK-8(ns) in the CNS has hitherto generally been neglected. Our results point to the equivalence of CCK-8(s) and CCK-8(ns) in the CNS in most biological tests. In some cases the latter compound is the more potent one. In most of these tests the C-terminal fragment (tetragastrin = CCK-4) also proved to be active. It is most likely that a brain receptor population exists which can bind both forms of CCK-8 and even CCK-4. Nevertheless, the CNS could contain binding sites which bind only CCK-8(s) as a ligand. We have found that an unidentified sulfotransferase of the brain can sulfate CCK-8(ns) and thereby provide a ligand for the special receptors of CCK-8(s). It is likely that CCK modulates the turnover and release of DA, and vice versa. Theoretically, different biochemical mechanisms could exist for interactions between CCK octapeptides and DA. We have focused our investigations on the enzymic sulfation-desulfation processes of both CCK-8 and DA and have devised a hypothetical model for the possible interactions. Both CCK-8(ns) and DA could be sulfated in vivo, this enzymic reaction generally requiring active sulfate (PAPS). These two compounds could compete for the limited pool of PAPS, and thus CCK-8 and DA could mutually regulate their levels in the same cell by influencing one of the metabolic (DA) or synthetic (CCK-8(s)) pathways. CCK-8(s) also might provide the O-sulfate group for DA by enzymic transformation, and, conversely, DA-O-sulfate may sulfate CCK-8(ns) in a similar way. These trans-sulfation processes could also mutually determine the concentrations of DA and CCK-8 co-existing in one cell. Experiments to prove these models are planned.
Penke
B
B
Kovács
G L
GL
Zsigó
J
J
Kádár
T
T
Szabó
G
G
Kovács
K
K
Telegdy
G
G
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D018377:Neurotransmitter Agents / Q000502:physiology; D051381:Rats; D012844:Sincalide / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D013464:Sulfuric Acids / Q000378:metabolism*; D013466:Sulfurtransferases / Q000032:analysis; D014316:Tritium
D018377:Neurotransmitter Agents; D013464:Sulfuric Acids; D014316:Tritium; D013466:Sulfurtransferases; D012844:Sincalide; D004298:Dopamine