Direct modulation of TRPC ion channels by Gα proteins

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 7, 2024

GPCR-G i protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and closely associated with internal visceral organs. The receptor-operated cationic channel is important signal transduction as it decreases heart rate increases GI rhythm frequency. In SA node heart, acetylcholine binds to M2 receptor released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. gastric smooth muscle, there two (mAChR) subtypes, M3. nonselective current (mIcat, NSCC(ACh)) induces positive effect. Meanwhile, M3 hydrolysis PIP 2 releases DAG IP 3 . This intracellular Ca 2+ then leads contraction muscles. activation mIcat inhibited by anti-G i/o antibodies indicating involvement Gα mIcat. TRPC4 molecular candidate for can be directly activated constitutively active QL proteins. TRPC5 belong same subfamily both G Initial studies suggested that binding sites exist at rib helix or CIRB domain TRPC4/5 channels. However, recent cryo-EM structure showed IYY 58-60 amino acids ARD i3 protein. Considering expression brain, direct on terms neurophysiology. channels also coincidence detector q increased facilitates More complicated situation would occur when GIRK, KCNQ2/3 (I M ) co-activated stimulation receptors acetylcholine-releasing nerve terminals. review highlights effects pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, various oragns, emphasizes importance considering crucial players field neuroscience.

Language: Английский

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Neuroscience in Ukraine

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110353 - 110353

Published: Feb. 1, 2025

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Physical Exercise Alleviates Oxidative Stress and Autonomic Dysregulation in a Rat Model of Inflammatory Bowel Disease

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 328 - 328

Published: March 10, 2025

Inflammatory bowel disease (IBD) induces immunological and autonomic imbalances. Exercise is a beneficial strategy for controlling IBD symptoms. We investigated the role of exercise on gastrointestinal (GI) motility changes parameters in rats with ileitis. Rats were divided into control, ileitis, exercise+ileitis groups. Ileitis was induced by TNBS (40 mM, intraileally). The swimming (1 h/day/4 weeks, 5%/bw). assessed eating behaviour oxidative stress. Body composition bioimpedance. Autonomic balance ECG measured an electrocardiogram (ECG). Gastrointestinal evaluated using phenol red technique. In terms body composition, total water (TBW), mass index (BMI), fat-free (FFM) higher ileitis group (216.80 ± 11.44 mL; 24.09 2.15 g/cm2; 287.1 14.66 g) (p < 0.05) vs. control (130.06 28.23 16.38 2.50 193 42.21 prevented (91.33 12.33 11.73 0.47 133.8 16.82 these changes. reduction gastric retention (11.22 1.91% 35.17 1.01% 33.96 1.77%). increased intestinal duodenum (46.3 2.56% 24.98 1.78%) jejunum (34.22 2.33% 34.72 2.83% 47.32 1.48%) decreased ileum group. Exercise+ileitis (24.96 1.66% 46.3 2.56%) (40.32 3.75% 14.08 0.88%). high MDA levels (4.43 0.69 0.12 nmol/mg tissue). This effect (2.75 0.21 4.43 observed LF component (31.32 3.99 43.43 3.86). correlation indicated stronger interrelationship between parameter (r: 0.68; p: 0.04). current study suggests alters GI balance, physical can represent essential non-pharmacological approach to treatment.

Language: Английский

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Synergistic effects of Ligilactobacillus salivarius Li01 and psyllium husk prevent mice from developing loperamide-induced constipation

Food & Function, Journal Year: 2024, Volume and Issue: 15(24), P. 11934 - 11948

Published: Jan. 1, 2024

Ligilactobacillus salivarius Li01 and psyllium husk protect mice treated with loperamide from constipation.

Language: Английский

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Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 13, 2024

ABSTRACT Directly probing the endogenous biological roles of target proteins with high spatial and temporal resolution, as non-invasively reproducibly possible, is a shared conceptual goal for research across many fields, well targeted therapies. Here we describe rational design test-case practical implementation photopharmacological paradigm to empower high-performance photomodulation studies in vivo . TRPC4/5 ion channels are involved spatiotemporally resolved circuits, from pain anxiety, reproductive signaling, digestion, obesity. To unpick their biology requires precise tools, which were lacking. We developed “ideal efficacy photoswitch” ligands control diverse functions situ These E ⇆ Z- photoswitchable bias TRPC[4]/5 channel activity exquisite photocontrol, strong agonism under 360 nm, low at 385 antagonism 410-460 nm. Cryo-EM structures both TRPC4 TRPC5 agonists E- antagonists support rationale switching through competitive E/Z isomer binding. Crucially, since ratio exclusively determined by light wavelength applied, photocontrol wavelength-dependent, yet drug-concentration-independent: so reproducible cell culture >millimetre-depth tissues Indeed, able direct downstream lines or primary cells culture, calcium flux, neuron excitability adrenaline release; even tissues, photoswitching small intestine motility peristalsis. The develop will thus unlock range high-precision investigations TRP biology. More broadly, propose that success this photoswitch program, concept tissue level translation, mainly consequence how has evolved control. therefore foresee variety functionally responsive protein targets, not only sensory signaling receptors, be amenable similarly , if new generation reagent development adopts ideal Table Contents Graphic

Language: Английский

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Magnetic Resonance Imaging of Gastric Motility in Conscious Rats

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 13, 2024

Abstract Introduction Gastrointestinal (GI) magnetic resonance imaging (MRI) can simultaneously capture gastric peristalsis, emptying, and intestinal filling transit. Performing GI MRI with animals requires anesthesia, which complicates physiology confounds interpretation translation from to humans. This study aims enable in conscious rats, for the first time, characterize motor functions awake versus anesthetized conditions. Methods We acclimated rats remain awake, still, minimally stressed during MRI. scanned 14 Sprague-Dawley both conditions after voluntarily consuming a contrast-enhanced test meal. Results Awake remained physiologically stable MRI, showed emptying of 23.7±1.4% 48 minutes, exhibited strong peristaltic contractions propagating through antrum velocity 0.72±0.04 mm/s, relative amplitude 40.7±2.3%, frequency 5.1±0.1 cycles per minute. In condition, was about half that likely due effect anesthesia halving amplitudes rather than their (not significantly changed) or velocity. intestine filled more quickly propulsive were occlusive. Conclusion demonstrated effective acquisition analysis rats. show faster stronger contraction propagation speed, transit, compared Our protocol is expected benefit future preclinical studies pathophysiology.

Language: Английский

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Cannabidiol inhibits transient receptor potential canonical 4 and modulates excitability of pyramidal neurons in mPFC

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 13, 2024

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been extensively studied for its potential therapeutic effects on various central nervous system (CNS) disorders, including epilepsy, chronic pain, Parkinson’s disease, and stress-related neuropsychiatric disorders. However, pharmacological mechanisms of CBD have not fully elucidated due to complexity their targets. In this study, we reported that transient receptor canonical 4 (TRPC4) channel, calcium-permeable, non-selective cation could be inhibited by CBD. TRPC4 is highly abundant in plays critical role regulating axonal regeneration, neurotransmitter release, neuronal network activity. Here, used whole-cell electrophysiology intracellular calcium measurements identify inhibitory TRPC4, which was found inhibit channel with an IC 50 value 1.52 μM channels function as receptor-operated (ROC) activated epinephrine (EP) via G proteins. We show can EP-evoked current vitro excitability medial prefrontal cortex (mPFC). These results are consistent action TRPC4-specific inhibitor Pico145, suggesting works functional ionotropic This study identified novel target CNS suggested reduce pyramidal neuron inhibiting TRPC4-containing mPFC.

Language: Английский

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Magnetic Resonance Imaging of Gastric Motility in Conscious Rats

Neurogastroenterology & Motility, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Gastrointestinal (GI) magnetic resonance imaging (MRI) enables simultaneous assessment of gastric peristalsis, emptying, and intestinal filling transit. However, GI MRI in animals typically requires anesthesia, which complicates physiology confounds interpretation translation to humans. This study aimed establish conscious rats, for the first time, characterize motor functions awake versus anesthetized conditions.

Language: Английский

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