Genetic mutation of TRPV2 induces anxiety by decreasing GABA-B R2 expression in hippocampus

Liu, Gaoyan; Niu, Bowen; Zhou, Yu; Peng, Qingyu; Yan, Jin; Tang, Yunfei; Chen, Fuxue; Li, Feng; Feng, Shini

doi:10.1016/j.bbrc.2022.06.079

Cited by 4 publications

(3 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like TRPV1, TRPV2 is also a Ca 2+ permeable channel strongly activated and desensitized by cannabidiol (de Petrocellis et al, 2011; Pumroy et al, 2019). TRPV2 is mainly involved in peripheral nociception, but there is recent evidence suggesting that it may play a role in both autism and epilepsy, as genetic mutation of this channel leads to autistic behaviours and network hyperexcitability (Liu et al, 2022). TRPV2 activation has known anxiolytic effects (van den Burg et al, 2015) and, as adult R59X mice have reduced TRPV2 expression in the cortex, it is conceivable that the observed effects of cannabidiol on social behaviour may involve the augmentation of this diminished system.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5^R59X knock‐in mice

Li,

Yennawar,

Wiest

et al. 2024

Eur J of Neuroscience

View full text Add to dashboard Cite

Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss‐of‐function mutation in CDKL5 gene, encoding a serine–threonine kinase highly expressed in the brain. CDD manifests with early‐onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock‐in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre‐treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long‐term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild‐type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G‐coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild‐type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

show abstract

Section: Discussionmentioning

confidence: 99%

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5^R59X knock‐in mice

Li,

Yennawar,

Wiest

et al. 2024

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…Under physiological conditions, cell surface expression of GABA B receptors is precisely controlled by constitutive endocytosis, recycling, degradation, and new synthesis of receptors [33]. However, under pathological conditions, GABA B receptors are commonly downregulated, compromising a healthy excitation/inhibition balance [12][13][14][15][16][17][18]. Pathological downregulation of GABA B receptors is associated with inhibition of fast receptor recycling and increased sorting of the receptors to lysosomes for degradation [19][20][21]31,34,35].…”

Section: Discussionmentioning

confidence: 99%

“…In neurological diseases associated with a disturbed excitation/inhibition balance, such as anxiety, addiction, depression, neurodegenerative diseases, and cerebral ischemia, GABA B receptors are downregulated and thus are no longer able to counteract pathologically increased neuronal activity [12][13][14][15][16][17][18]. A major insight into a mechanism downregulating GABA B receptors came from studies on neuronal excitotoxicity and cerebral ischemia, which are extreme examples of a disturbed excitation/inhibition balance.…”

Section: Introductionmentioning

confidence: 99%

ERK1/2-Dependent Phosphorylation of GABAB1(S867/T872), Controlled by CaMKIIβ, Is Required for GABAB Receptor Degradation under Physiological and Pathological Conditions

Bhat,

Grampp,

Benke

2023

IJMS

View full text Add to dashboard Cite

GABAB receptor-mediated inhibition is indispensable for maintaining a healthy neuronal excitation/inhibition balance. Many neurological diseases are associated with a disturbed excitation/inhibition balance and downregulation of GABAB receptors due to enhanced sorting of the receptors to lysosomal degradation. A key event triggering the downregulation of the receptors is the phosphorylation of S867 in the GABAB1 subunit mediated by CaMKIIβ. Interestingly, close to S867 in GABAB1 exists another phosphorylation site, T872. Therefore, the question arose as to whether phosphorylation of T872 is involved in downregulating the receptors and whether phosphorylation of this site is also mediated by CaMKIIβ or by another protein kinase. Here, we show that mutational inactivation of T872 in GABAB1 prevented the degradation of the receptors in cultured neurons. We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. Blocking ERK activity after subjecting neurons to ischemic stress completely restored downregulated GABAB receptor expression to normal levels. Thus, preventing ERK1/2-mediated phosphorylation of S867/T872 in GABAB1 is an opportunity to inhibit the pathological downregulation of the receptors after ischemic stress and is expected to restore a healthy neuronal excitation/inhibition balance.

show abstract

Outlining auriculotherapy in anxiety as an evidence-based medicine: A brief overview

Vieira,

Moreira,

Machado

2023

Revista Internacional de Acupuntura

View full text Add to dashboard Cite

Genetic mutation of TRPV2 induces anxiety by decreasing GABA-B R2 expression in hippocampus

Cited by 4 publications

References 31 publications

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5^R59X knock‐in mice

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5^R59X knock‐in mice

ERK1/2-Dependent Phosphorylation of GABAB1(S867/T872), Controlled by CaMKIIβ, Is Required for GABAB Receptor Degradation under Physiological and Pathological Conditions

Outlining auriculotherapy in anxiety as an evidence-based medicine: A brief overview

Contact Info

Product

Resources

About

Genetic mutation of TRPV2 induces anxiety by decreasing GABA-B R2 expression in hippocampus

Cited by 4 publications

References 31 publications

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock‐in mice

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock‐in mice

ERK1/2-Dependent Phosphorylation of GABAB1(S867/T872), Controlled by CaMKIIβ, Is Required for GABAB Receptor Degradation under Physiological and Pathological Conditions

Outlining auriculotherapy in anxiety as an evidence-based medicine: A brief overview

Contact Info

Product

Resources

About

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5^R59X knock‐in mice

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5^R59X knock‐in mice