Pteropodine and isopteropodine positively modulate the function of rat muscarinic M(1) and 5-HT(2) receptors expressed in Xenopus oocyte.
Pteropodine and isopteropodine are heteroyohimbine-type oxindole alkaloid components of Uncaria tomentosa (Willd.) DC, a Peruvian medicinal plant known as cat's claw. In this study, the effects of these alkaloids on the function of Ca(2+)-activated Cl(-) currents evoked by stimulation of G protein-coupled muscarinic M(1) acetylcholine and 5-HT(2) receptors were studied in Xenopus oocytes in which rat cortex total RNA was translated. Pteropodine and isopteropodine (1-30 microM) failed to induce membrane current by themselves. However, these alkaloids markedly enhanced the current responses evoked by both acetylcholine and 5-hydroxyhyptamine (5-HT) in a concentration-dependent and reversible manner with the maximal effects at 30 microM. Pteropodine and isopteropodine produced 2.7- and 3.3-fold increases in the acetylcholine response with EC(50) values of 9.52 and 9.92 microM, respectively, and 2.4- and 2.5-fold increases in the 5-HT response with EC(50) values of 13.5 and 14.5 microM, respectively. In contrast, in oocytes injected with total RNA from the rat cerebellum or spinal cord, neither alkaloid had an effect on the metabotropic current responses mediated by glutamate receptor(1 and 5) (mGlu(1/5)) receptors or ionotropic responses mediated by N-methyl-D-aspartate, kainic acid or glycine. Pteropodine and isopteropodine (10 microM) significantly reduced the EC(50) values of acetylcholine and 5-HT that elicited current responses, but had no effect on the maximal current responses elicited by acetylcholine and 5-HT. On the other hand, mitraphylline, a stereoisomer of pteropodine, failed to modulate acetylcholine- and 5-HT-induced responses. These results suggest that pteropodine and isopteropodine act as positive modulators of muscarinic M(1) and 5-HT(2) receptors.
Department of Pharmacology, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, 930-0194, Japan.
Tai-Hyun
TH
Kang
Kinzo
K
Matsumoto
Michihisa
M
Tohda
Yukihisa
Y
Murakami
Hiromitsu
H
Takayama
Mariko
M
Kitajima
Norio
N
Aimi
Hiroshi
H
Watanabe
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009865:Oocytes; D000078183:Oxindoles; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D013237:Stereoisomerism; D014981:Xenopus
D000470:Alkaloids; D007211:Indoles; D000078183:Oxindoles; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D013141:Spiro Compounds; C431786:uncarine E; C431785:uncarine C