Abstract
The M-channel is a neuronal ion channel complex that is important for stabilizing neurons at subthreshold potential, limiting continuous neuronal firing. The M-channel belongs to the KV7 channel family and is formed mainly by KV7.2/KV7.3 heteromultimers. The physiological importance of the M-channel is evident by channel mutations that have been linked to an inherited form of juvenile epilepsy. We have previously described that polyunsaturated fatty acids activate the M-channel and thereby dampen neuronal excitability. Several members within the large family of endocannabinoids are structurally related to polyunsaturated fatty acids. We therefore hypothesize that endocannabinoids may modulate the activity of the M-channel. To test that hypothesis, we studied the effect of different endocannabinoids on the human KV7.2/KV7.3 channel expressed in Xenopus oocytes, using two-electrode voltage clamp. We found that specific compounds belonging to the endocannabinoid family activate the M-channel by shifting the voltage dependence of channel opening towards negative voltages and increasing the maximal conductance. In particular, N-Arachidonoyl L-serine (ARA-S) had a large activating effect, with significant effects from 0.3 μM. In contrast, some of the most commonly known endocannabinoids, e.g. 2-Arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide), did not activate the M-channel. From a systematic comparison of compounds with distinct chemical properties, we conclude that a negative charge of the head group is crucial for the activating effect, whereas the specific length and number of double bonds of the acyl tail is less important. Altogether, these findings suggest that specific members within the family of endocannabinoids may signal non-canonically via the M-channel. Understanding which endocannabinoids target the M-channel is of importance for interpretation of endocannabinoid effects on neuronal excitability and may be utilized for future development of pharmaceutical agents.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
