The leucokinins are small insect neuropeptides which were originally isolated from head extracts of the Madeira cockroach, Leucophaea maderae. They stimulate the contractions of the cockroach's lower digestive tract.

Identification of leucokinins and their cognate receptors has been successfully undertaken in cockroach, Leucophaea maderae, including the genetically tractable Dipteran, Drosophila Melanogaster, progress has been made in studies of leucokinin signalling in biomedically relevant insects.1, 2, 3.

Structural Characteristics
Leucokinins I and III are flanked by dibasic proteolytic cleavage sites, and in all three peptides a C-terminal Gly is present, which is predicted to be processed into a C-terminal amide group in the mature peptides. A different proteolytic cleavage site is present at the N terminus of leucokinin II, consisting of a single Arg with a Lys at residue –8. Four Cys residues are also present in the protein region before to the leucokinin peptide sequences. The position of the four Cys residues is identical, suggesting that these residues may play an important role in the function of the precursor protein, perhaps in the formation of disulphide bridges. It has been proposed that these residues are responsible for paraldehyde 4.

Mode of Action
Leucokinins in the cockroach increase motility of the isolated hindgut. Surprisingly, synthetic leucokinins have biological activity in a different insect and in a different tissue. In isolated Malpighian tubules of the yellow fever mosquito Aedes aegypti, leucokinins depolarize the transepithelial voltage. This effect on voltage is dependent on extracellular Cl. One leucokinin, LK-8, the effects of which were studied further in isolated Malpighian tubules, was found to inhibit transepithelial fluid secretion at low concentrations and to stimulate fluid secretion at high concentrations. The depolarizing effects on voltage and the stimulation of fluid secretion suggest that leucokinins increase the Cl permeability of the tubule wall thereby increasing the availability of Cl for secretion with Na, K and water. Structure-function comparisons of the seven leucokinins studied suggest that the active region of the octapeptide is segregated to the C-terminal pentapeptide. In view of the known effects of leucokinins on hindgut motility in the cockroach, finding of effects in mosquito Malpighian tubules suggests that leucokinins may be widely distributed in insects where they may have diverse functions in a variety of organs 5.

Leucokinins act on the leucokinin receptor to raise intracellular calcium having identified both leucokinins and a leucokinin-like receptor within Anopheles, it was established that they are a functional receptor–ligand pairing. The action of leucokinins on tubules were consistent with the existence of more than one receptor and that the broad concentration range of Drosophila leucokinin on Drosophila tubule was also taken as suggestive of multiple receptor classes.

Cross-specific leucokinin signaling, the effects of the Anopheles leucokinins on S2 cells expressing the Drosophila LKR, CG10626 were also established. Drosophila leucokinin was found to stimulate the A. stephensi receptor in a similar manner to the Anopheles leucokinins, displaying an EC50 value of 1.1•nmol, very similar to that of Anopheles leucokinin I.

Drosophila leucokinin was also found to activate the Anopheles receptor with a similar EC50 value to Anopheles leucokinin I. However, when the Anopheles peptides were applied to the Drosophila receptor, only Anopheles leucokinin I and II elicited a rise in Ca2+. This suggests that the Anopheles receptor has a broader specificity for leucokinin ligands than the Drosophila receptor 6. The insect leucokinins have attracted a great deal of interest as lead molecules for novel pesticides, including the development of peptidase resistant analogues of this family of peptides. Insect leucokinins have diverse roles; they act via their cognate G protein-coupled receptors (GPCRs). Furthermore, as leucokinins have only been found in invertebrates, it is likely that careful design of leucokinin antagonist or agonist analogues will avoid interactions with mammalian species. Recent studies have suggested the involvement of leucokinins in dietary regulation and energy mobilisation 6.

1. Holman GM, Cook BJ, Wagner RM (1984). Isolation and partial characterization of five myotropic peptides present in head extracts of the cockroach, Leucophaea maderae. Comp. Biochem. Physiol., 77(1):1-5.
2. Holman GM, Nachman RJ Coast GM (1999). Isolation, characterization and biological activity of a diuretic myokinin neuropeptide from the housefly, Musca domestica. Peptides, 20:1-10.
3. Terhzaz S, O’Connell FC, Pollock, VP, Kean L, Davies SA, Veenstra, JA, Dow, JAT (1999). Isolation and characterization of a leucokinin-like peptide of Drosophila melanogaster. J Exp Biol., 202:3667-3676.
4. Veenstra JA, Pattillo JM, Petzel DH (1997). A single cDNA encodes all three Aedes leucokinins, which stimulate both fluid secretion by the Malpighian tubules and hindgut contractions. J. Biol. Chem., 272:10402- 10407.
5. Hayes TK, Pannabecker TL, Hinckley DJ, Holman GM, Nachman RJ, Petzel DH,     Beyenbach KW (1989). Leucokinins, a new family of ion transport stimulators and inhibitors in insect Malpighian tubules. Life Sci., 44(18):1259-1266.
6. Radford JC, Terhzaz S, Cabrero P, Davies SA, Dow JA (2004). Functional characterisation of the Anopheles leucokinins and    their cognate G-protein coupled receptor. The Journal of Experimental Biology, 207

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