Structural determinants of lolitrems for inhibition of BK large conductance Ca2+-activated K+ channels.
Lolitrem B is an indole-diterpenoid neurotoxin which is the main causative agent of ryegrass staggers, an animal disease associated with tremors and incoordination. It is also a potent inhibitor of large conductance calcium-activated potassium (BK) channel activity (IC(50)=4 nM). Furthermore, we have recently shown that the motor function deficits induced by lolitrem B are specifically mediated by BK channels, making the toxin a valuable tool for investigating the molecular function and physiological roles of these channels. To determine what structural features of BK channel agents are required for high potency, the effect of lolitrem B and seven structurally-related lolitrems on BK channel activity has been measured. Concentration-responses and conductance-voltage (G-V) relationships were determined for each compound and related to the different structure types. This study has identified seven new BK channel inhibitors and has allowed the identification of two key structural features required for high potency BK channel activity by lolitrems.
Imlach
Wendy L
WL
AgResearch, Grasslands Research Centre, Palmerston North 4442, New Zealand.
Finch
Sarah C
SC
Dunlop
James
J
Dalziel
Julie E
JE
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D026121:Indole Alkaloids; D020128:Inhibitory Concentration 50; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D009183:Mycotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009498:Neurotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D026121:Indole Alkaloids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009183:Mycotoxins; D009498:Neurotoxins; D026902:Potassium Channel Blockers; C033673:lolitrem B