Ca2+-entry blockade by CAF603, a carotane sesquiterpene isolated from Trichoderma virens

Area of Science:

• Pharmacology
• Myology
• Natural Products Chemistry

Background:

• 8-daucene-3,4-diol (CAF603) is a sesquiterpene isolated from the fungus Trichoderma virens.
• Sesquiterpenes are known to possess diverse biological activities, warranting investigation into their pharmacological effects.

Purpose of the Study:

• To investigate the functional effects and underlying mechanisms of action of CAF603 on smooth muscle tissues.
• To determine the specific ion channels modulated by CAF603.

Main Methods:

• Isometric tension recordings were performed on guinea-pig portal vein, duodenum, ileum, and detrusor muscle.
• Patch-clamp electrophysiology was used to record L-type Ca2+ channel currents in rabbit cardiac myocytes.
• Effects were assessed in response to various stimuli including spontaneous activity, Ca2+-induced contraction, and high-KCl depolarization.

Main Results:

• CAF603 (1-100 microM) inhibited spontaneous motility in portal vein, duodenum, and ileum, and Ca2+-induced tension in ileum.
• CAF603 increased spontaneous motility of guinea-pig detrusor muscle but inhibited high-KCl-induced contractions.
• CAF603 blocked L-type Ca2+ channel currents in rabbit cardiac myocytes and modulated charybdotoxin binding to BKCa channels.

Conclusions:

• CAF603 exhibits dual effects on smooth muscle, inhibiting contractility via Ca2+-entry blockade and stimulating detrusor motility through blockade of Ca2+-activated K+ (BKCa) channels.
• These findings suggest CAF603 as a potential therapeutic agent targeting smooth muscle function.
• The study elucidates novel mechanisms of action for a fungal sesquiterpene on ion channel activity.