Kyotorphins

Definition
Kyotorphins are endogenous peptides that take part in the regulation of various adaptive reactions of the organism. They play a role in pain modulation in the mammalian CNS (central nervous system).

Discovery
Kyotorphins (Tyr-Arg) is a dipeptide originally found in bovine and rat brain synaptosomes, is formed from tyrosine and arginine by a specific synthetase. Kyotorphins is a neuroactive peptide named after its place of discovery, Kyoto, Japan1. It has a specific receptor coupled to G i and phospholipase C and elicits enkephalin release.

Structural Characteristics
At biological pH kyotorphins have a neutral net charge. The phenolic rings interact with phospholipid molecules (partition coefficient varies from 6 × 102 to 2 × 104, depending on the lipid and pH used) despite being exposed to the aqueous bulk medium. The lowest energy transition dipole moment is displaced from the normal to the lipid bilayer by 20° on average. The observed extensive interaction, pKa, precise location, and well-defined orientation in membranes combined with the ability to discriminate rigid raft like membrane domains suggest that kyotorphin meets the structural constraints needed for receptor-ligand interaction. The acylated kyotorphin derivative mimics kyotorphin properties and represents a promising way for entrapment in a drug carrier and transport across the blood-brain barrier 2.

Mode of Action
Previous studies suggested that kyotorphin-induced opioid like analgesia may be mediated via a release of Met-enkephalin from the brain. Kyotorphin elicited a release of Met-enkephalin from brain slices but not of [3H]-noradrenaline, [3H]-GABA, [3H]-aspartate and endorphin. The neurochemical basis of mechanisms suggests that Kyotorphins stimulates its specific receptor, followed by G i and phospholipase C (PLC) activations. PLC mechanism leads to a Ca2+ influx in nerve ending particles or synaptosomes. Inositol 1, 4, 5-trisphosphate (InsP3) elicits Ca2+ transport through plasmalemmal InsP3 receptor but not through intra synaptosomal Ca2+ stores. Kyo-induced antinociceptive responses are mediated through its specific receptor. However, at extremely low doses (below femtomolar ranges) of nociceptin/orphanin the endogenous ligand of opioid receptor-like orphan receptor it is coupled to G i, elicits nociceptive responses through its receptor and G i. Potent peripheral nociceptive action of Kyo occur through an InsP3-receptor-gated Ca2+ influx 3,4.

Functions
Kyotorphin improve cardiovascular and cerebral resuscitation after heart arrest - The rate of post resuscitational restoration and survival after a 12-min heart arrest shows that kyotorphin accelerates restoration of vital functions, improve cardiovascular and neurological status within several days after resuscitation 5.

Kyotorphin synthetase activity in rat adrenal glands and spinal cord- Kyotorphin is formed by kyotorphin synthetase from its constituent amino acids, L-Tyr and L-Arg, in the brain in an ATP-Mg2+-dependent manner. To elucidate the physiological role of kyotorphin in organs other than the brain, Kawabata et al., have examined the activity of kyotorphin synthetase in the rat adrenal glands and spinal cord. The activity of adrenal kyotorphin synthetase was inhibited by some L-Arg analogues. Activity was inhibited by NG-nitro-L-arginine methyl ester, alpha-methyl-L-ornithine and D-Arg, but not by NG-nitro-L-arginine and N-iminoethyl-L-ornithine. In the crude soluble extracts from the adrenal glands and spinal cord, kyotorphin was formed by kyotorphin synthetase, and also by the enzymatic processing of the precursor proteins, in the presence of physiological concentrations of L-Tyr and L-Arg in addition to ATP and MgCl2. Kyotorphin synthetase resembling that in the brain is also found to present in the rat adrenal glands and spinal cord, helps in the formation of kyotorphin6.

Kyotorphin suppresses proliferation and Ca2+ signaling in brown preadipocytes-Kyotorphin abolished the stimulatory effect of norepinephrine on proliferation of cultured cells and cold-induced [3H]-thymidine incorporation into DNA of mouse brown adipose tissue in vivo. These changes correlated with peptide-induced suppression of slow calcium signalling in brown preadipocytes.

References
1.Takagi H, Shiomi H, Ueda H, Amano H (1979). A novel analgesic dipeptide from bovine brain is a possible Met-enkephalin release. Nature, 282(5737):410–412.
2.Lopes SC , Soares CM, Baptista AM, Goormaghtigh E, Cabral B , Castanho MA (2006). Conformational and Orientational Guidance of the Analgesic Dipeptide Kyotorphin Induced by Lipidic Membranes: Putative Correlation toward Receptor Docking. J Phys Chem., 110(7):3385–3394.
3.Cheng ZJ, Fan GH, Zhao J, Zhang Z, Wu YL, Jiang LZ, Zhu Y, Pei G, Ma L (1997). Endogenous opioid receptor-like receptor in human neuroblastoma SK-N-SH cells: Activation of inhibitory G protein and homologous desensitization. Neuroreport., 27:1913-1918.
4.Inoue M, Kobayashi M, Kozaki S, Zimmer A, Ueda H (1998). Nociceptin/orphanin FQ-induced nociceptive responses through substance P release from peripheral nerve endings in mice. PNAS, 95:10949-10953.
5.Kharchenko IB, Ziganshin RK, Volkov AV, Koshelev VB (1997). Neokyotorphin and kyotorphin improve cardiovascular and cerebral resuscitation after heart arrest. Bulletin of Experimental Biology and Medicine, 123:450-452.
6.Kawabata A, Muguruma H, Tanaka M, Takagi H (1996). Kyotorphin synthetase activity in rat adrenal glands and spinal cord. Peptide, 17:407-411.