Inhibition of Ca<sub>v</sub>3.2 calcium channels: A new target for colonic hypersensitivity associated with low‐grade inflammation

Picard, Elodie; Carvalho, Frédéric A.; Agosti, Francina; Bourinet, Emmanuel; Ardid, Denis; Eschalier, Alain; Daulhac, Laurence; Mallet, Christophe

doi:10.1111/bph.14608

Cited by 28 publications

(31 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This model contrasts with the post-inflammatory model of high-dose DSS followed by a recovery period, discussed in the next paragraph. An overexpression of the T-type calcium channel cav3.2 in this model, which was also observed in colonic biopsies of IBS patients, was associated with colonic hypersensitivity in this model ( 163 , 164 ).…”

Section: Low Grade Inflammatory Post-infectious and Post-inflammatorsupporting

confidence: 63%

Animal Models for Functional Gastrointestinal Disorders

Accarie

Vanuytsel

2020

Front. Psychiatry

View full text Add to dashboard Cite

Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.

show abstract

Section: Low Grade Inflammatory Post-infectious and Post-inflammatorsupporting

confidence: 63%

Animal Models for Functional Gastrointestinal Disorders

Accarie

Vanuytsel

2020

Front. Psychiatry

View full text Add to dashboard Cite

show abstract

“…While the mechanism(s) underlying this are still unknown, inhibition of T-Type ICa is a possible contributor. 58,59…”

Section: Discussionmentioning

confidence: 99%

Modulation of Recombinant Human T-type calcium Channels by Δ⁹-tetrahydrocannabinolic acid in vitro

Mirlohi

Bladen

Santiago

et al. 2020

Preprint

View full text Add to dashboard Cite

Introduction: Low voltage-activated T-type calcium channels (T-type ICa), CaV3.1, CaV3.2, and CaV3.3 are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders including absence epilepsy and pain. Δ9-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type ICa , however, there is no information about functional activity of most phytocannabinoids on T-type ICa, including Δ9-tetrahydrocannabinol acid (THCA), the natural non-psychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type ICa . Materials and Methods: We used HEK293 Flp-In-TREx cells stably expressing CaV3.1, 3.2 or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of ICa . Results: THCA and THC inhibited the peak current amplitude CaV3.1 with a pEC50s of 6.0 ± 0.7 and 5.6 ± 0.4, respectively. 1 μM THCA or THC produced a significant negative shift in half activation and inactivation of CaV3.1 and both drugs prolonged CaV3.1 deactivation kinetics. THCA (10 μM) inhibited CaV3.2 by 53% ± 4 and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of CaV3.2. THC prolonged the deactivation time of CaV3.2 while THCA did not. THCA inhibited the peak current of CaV3.3 by 43% ± 2 (10μM) but did not notably affect CaV3.3 channel activation or inactivation, however, THC caused significant hyperpolarizing shift in CaV3.3 steady state inactivation. Discussion: THCA modulated T-type ICa currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy via T-type channel modulation without the unwanted psychoactive effects associated with THC

show abstract

“…Non‐parametric two‐tailed Wilcoxon signed‐rank test was used to evaluate matched data (Figure 3b, synchronized events, and Figure S1b). In the plots of multiple groups, non‐parametric statistical comparison was evaluated by Kruskal–Wallis test followed by pairwise Mann–Whitney U test for two independent groups (Figures 2b, 3a, 4b, and 5c; Kodama et al, 1999; Snyder et al, 2003; Picard et al, 2019) or by Friedman test followed by pairwise Wilcoxon signed‐rank test for matched data (Figure S1a). Post hoc tests were only conduced when the Kruskal–Wallis test or Friedman test is significant ( P < 0.05).…”

Section: Methodsmentioning

confidence: 99%

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations

Yang

Wang

Chuang

et al. 2020

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose: Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored. Experimental Approach: The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling. Key Results: Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABA A receptor antagonist bicuculline, which is usually considered as a proconvulsant. Conclusion and Implications: Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.

show abstract

Inhibition of Ca_v3.2 calcium channels: A new target for colonic hypersensitivity associated with low‐grade inflammation

Cited by 28 publications

References 67 publications

Animal Models for Functional Gastrointestinal Disorders

Animal Models for Functional Gastrointestinal Disorders

Modulation of Recombinant Human T-type calcium Channels by Δ⁹-tetrahydrocannabinolic acid in vitro

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations

Contact Info

Product

Resources

About

Inhibition of Cav3.2 calcium channels: A new target for colonic hypersensitivity associated with low‐grade inflammation

Cited by 28 publications

References 67 publications

Animal Models for Functional Gastrointestinal Disorders

Animal Models for Functional Gastrointestinal Disorders

Modulation of Recombinant Human T-type calcium Channels by Δ9-tetrahydrocannabinolic acid in vitro

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations

Contact Info

Product

Resources

About

Inhibition of Ca_v3.2 calcium channels: A new target for colonic hypersensitivity associated with low‐grade inflammation

Modulation of Recombinant Human T-type calcium Channels by Δ⁹-tetrahydrocannabinolic acid in vitro