Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval

Hiniesto-Iñigo, Irene; Castro-González, Laura M.; Corradi, Valentina; Skarsfeldt, Mark Alexander; Lundholm, Siri; Nikesjö, Johan; Noskov, Sergei Y.; Bentzen, Bo Hjorth; Tieleman, D. Peter; Liin, Sara I.

doi:10.1016/j.ebiom.2023.104459

Cited by 6 publications

(2 citation statements)

References 69 publications

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“…CBD and other phytocannabinoids are meroterpenoids, whereas endocannabinoids are structurally similar to polyunsaturated fatty acids (PUFAs), another class of lipid that has been shown to modulate hK V 7 channels. Our laboratory has previously shown that the negatively charged head groups of polyunsaturated fatty acids and endocannabinoids form interactions with positively charged residues in the voltage‐sensing domain and pore domain of hK V 7.1 channels (Hiniesto‐Iñigo et al, 2023; Yazdi et al, 2021), while polyunsaturated fatty acids interact with other positively charged residues in hK V 7.4 (Frampton et al, 2022). CBD lacks charged moieties and as a result remains submerged in the lipid bilayer where it is unable to make the same interactions that polyunsaturated fatty acids and endocannabinoids make with channels.…”

Section: Discussionmentioning

confidence: 99%

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Pökl

Sridhar

Frampton

et al. 2023

British J Pharmacology

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Background and PurposeCannabidiol (CBD) is used clinically as an anticonvulsant. Its precise mechanism of action has remained unclear. CBD was recently demonstrated to enhance the activity of the neuronal KV7.2/7.3 channel, which may be one important contributor to CBD anticonvulsant effect. Curiously, CBD inhibits the closely related cardiac KV7.1/KCNE1 channel. Whether and how CBD affects other KV7 subtypes remains uninvestigated and the CBD interaction sites mediating these diverse effects remain unknown.Experimental ApproachHere, we used electrophysiology, molecular dynamics simulations, molecular docking and site‐directed mutagenesis to address these questions.Key ResultsWe found that CBD modulates the activity of all human KV7 subtypes and that the effects are subtype dependent. CBD enhanced the activity of KV7.2–7.5 subtypes, seen as a V50 shift towards more negative voltages or increased maximum conductance. In contrast, CBD inhibited the KV7.1 and KV7.1/KCNE1 channels, seen as a V50 shift towards more positive voltages and reduced conductance. In KV7.2 and KV7.4, we propose a CBD interaction site at the subunit interface in the pore domain that overlaps with the interaction site of other compounds, notably the anticonvulsant retigabine. However, CBD relies on other residues for its effects than the conserved tryptophan that is critical for retigabine effects. We propose a similar, though not identical CBD site in KV7.1, with a non‐conserved phenylalanine being important.Conclusions and ImplicationsWe identify novel targets of CBD, contributing to a better understanding of CBD clinical effects and provide mechanistic insights into how CBD modulates different KV7 subtypes.

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Section: Discussionmentioning

confidence: 99%

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Pökl

Sridhar

Frampton

et al. 2023

British J Pharmacology

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“…Furthermore, it is reported that OS displayed antagonist properties against TRPV1 channels overexpressed in HEK cells [35]. K V 7.1 channels are a target of the endocannabinoid AEA [36], which possesses structural similarities like the OS compound, as illustrated in Figure S1. Na V 1.5, K V 1.5, and K V 11.1 (hERG) were tested because they are critical for cardiac safety.…”

Section: Os Exhibits Selectivity For Cb Receptors Over Other Molecula...mentioning

confidence: 99%

The Sobering Sting: Oleoyl Serotonin Is a Novel Stephanoconus Snail Venom-Derived Antagonist of Cannabinoid Receptors That Counteracts Learning and Memory Deficits

An,

Carrazoni,

Souto das Neves

et al. 2024

Biomedicines

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Cannabinoid receptors (CB1 and CB2) are promising targets for a better understanding of neurological diseases. Nevertheless, only a few ligands of CB have reached clinical application so far. Venoms are considered as interesting sources of novel biologically active compounds. Here, we describe an endocannabinoid-like molecule, oleoyl serotonin (OS), present in the venom of Stephanoconus snails. Using electrophysiological assays, it was shown that OS inhibits CB1 and CB2. Structure–activity relationship studies using a chimeric CB1/2 revealed that the domain encompassing the transmembrane helix V (TMHV)– intracellular loop 3 (ICL3)–TMHVI of the CB2 is critical for the binding and function of OS. We concluded that OS binds to sites of the CB2 that are different from the binding sites of the non-selective CB agonist WIN55,212-2. Behavioral assays in mice showed that OS counteracted learning and memory deficits caused by WIN55,212-2. Furthermore, a selectivity screening of OS showed high selectivity for CB over various ion channels and receptors. Overall, OS may represent a new approach to the prevention and treatment of learning and memory cognition impairment in neurological diseases.

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The endocannabinoid ARA-S facilitates the activation of cardiac Kv7.1/KCNE1 channels from different species

Hiniesto-Iñigo,

Linhart,

Kusay

et al. 2024

Channels

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The endogenous endocannabinoid-like compound N-arachidonoyl-L-serine (ARA-S) facilitates activation of the human Kv7.1/KCNE1 channel and shortens a prolonged action potential duration and QT interval in guinea pig hearts. Hence, ARA-S is interesting to study further in cardiac models to explore the functional impact of such Kv7.1/KCNE1-mediated effects. To guide which animal models would be suitable for assessing ARA-S effects, and to aid interpretation of findings in different experimental models, it is useful to know whether Kv7.1/KCNE1 channels from relevant species respond similarly to ARA-S. To this end, we used the two-electrode voltage clamp technique to compare the effects of ARA-S on Kv7.1/KCNE1 channels from guinea pig, rabbit, and human Kv7.1/KCNE1, when expressed in Xenopus laevis oocytes. We found that the activation of Kv7.1/KCNE1 channels from all tested species was facilitated by ARA-S, seen as a concentration-dependent shift in the voltage-dependence of channel opening and increase in current amplitude and conductance over a broad voltage range. The rabbit channel displayed quantitatively similar effects as the human channel, whereas the guinea pig channel responded with more prominent increase in current amplitude and maximal conductance. This study suggests that rabbit and guinea pig models are both suitable for studying ARA-S effects mediated via Kv7.1/KCNE1.

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Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval

Cited by 6 publications

References 69 publications

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

The Sobering Sting: Oleoyl Serotonin Is a Novel Stephanoconus Snail Venom-Derived Antagonist of Cannabinoid Receptors That Counteracts Learning and Memory Deficits

The endocannabinoid ARA-S facilitates the activation of cardiac Kv7.1/KCNE1 channels from different species

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Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval

Cited by 6 publications

References 69 publications

Subtype‐specific modulation of human KV7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Subtype‐specific modulation of human KV7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

The Sobering Sting: Oleoyl Serotonin Is a Novel Stephanoconus Snail Venom-Derived Antagonist of Cannabinoid Receptors That Counteracts Learning and Memory Deficits

The endocannabinoid ARA-S facilitates the activation of cardiac Kv7.1/KCNE1 channels from different species

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Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

Subtype‐specific modulation of human K_V7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site