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Reactive oxygen species (ROS) produced by NADPH oxidase promote contraction of peripheral arteries, which is especially pronounced in early postnatal period in comparison to adulthood, but the mechanisms of such vasomotor influence are poorly understood. We tested the hypothesis that Rho-kinase and protein kinase C (PKC) mediate procontractile influence of NADPH oxidase derived ROS in peripheral artery of early postnatal rats. In addition, we evaluated the involvement Src-kinase and L-type voltage-gated Ca 2+ channels (LTCC) into procontractile influence of ROS, produced by NADPH oxidase, because of their known interplay with Rho-kinase and PKC pathways. Saphenous arteries from 11- to 15-day-old male rats were studied using quantitative PCR, isometric myography and lucigenin-enhanced chemiluminescence. Arterial tissue of early postnatal rats contained Nox2 , Nox4 , Duox1 and Duox2 mRNAs, among which Nox2 mRNA was the most abundant. Pan-NADPH oxidase inhibitor VAS2870 (10 µM) significantly reduced arterial contractile responses to methoxamine. The inhibitors of Rho-kinase (Y27632, 3 µM), PKC (GF109203X, 10 µM) and Src-kinase (PP2, 10 µM), as well as LTCC blockers (nimodipine, 0.1 µM, and verapamil, 0.1 μM) also reduced methoxamine-induced contraction. Importantly, the effect of VAS2870 persisted in the presence of Rho-kinase, PKC or Src-kinase inhibitors, but not in the presence of LTCC blocker. Notably, the blockade of LTCC did not affect either basal or NADPH-induced O 2 •- production. Our data show that LTCC, but not Rho-kinase, PKC or Src-kinase are involved into procontractile effect of ROS, produced by NADPH oxidase, in saphenous artery of young rats. Сalcium influx through LTCC does not activate ROS production by NADPH oxidase.

This proposed model explores the intricate Ca 2+ dynamics within the pancreatic acinar cells (PACs) by emphasizing the role of store-operated Ca 2+ entry (SOCE) and the mitochondrial-associated membranes (MAMs) in the secretory region (apical) of the PACs. Traditionally, Ca 2+ releases from the endoplasmic reticulum (ER) via calcium-induced calcium release (CICR). It has been shown to be important in regulating functions such as secretion of digestive enzymes in PACs. However, this model posits that upon the depletion of Ca 2+ in the ER, the signaling protein stromal interaction molecule (STIM1) is activated. Activated STIM1, then facilitates the opening of Orai channels, allowing Ca 2+ influx through the store-operated calcium channels (SOCCs). The model highlights the complexity of the Ca 2+ dynamics, and the importance of SOCE and MAMs in the PACs Ca 2+ homeostasis. The numerical and bifurcation analysis illustrate how changes in agonist concentrations can lead to the diverse Ca 2+ oscillation patterns, such as thin to broader oscillations, sinusoidal patterns, and baseline fluctuations, driven by the feedback mechanisms involving Ca 2+ and inositol 1,4,5 trisphosphate (IP 3 ). This understanding could have broader implications for cellular physiology and the development of therapies targeting Ca 2+ signaling pathways., Competing Interests: Compliance with ethical standards. Conflict of interest: The author declares no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholinergic tone is elevated in obstructive lung conditions such as chronic obstructive pulmonary disease (COPD) and asthma, but the cellular mechanisms underlying cholinergic contractions of airway smooth muscle (ASM) are still unclear. Some studies report an important role for L-type Ca 2+ channels (LTCC) and Ano1 Ca 2+ -activated Cl - channels (CACC) in these responses, but others dispute their importance. Cholinergic contractions of ASM involve activation of M3Rs, however, stimulation of M2Rs exerts a profound hypersensitization of these responses. Here, we show that M2R-dependent potentiation of cholinergic nerve-evoked contractions of ASM was reversed by the LTCC blocker nifedipine and the Ano1 CACC inhibitors Ani9 and CaCC inh -A01. Carbachol induced sustained contractions of ASM that were converted into oscillatory contractions when M3Rs were blocked with 4-DAMP. The 4-DAMP-resistant contractions were absent in preparations taken from M2R knockout (KO) mice. The remaining M2R-dependent responses, observed in wild-type (WT) mice, were abolished by nifedipine and Ani9. Inhibition of sarcoplasmic endoplasmic reticulum Ca 2+ ATPases (SERCA) with thapsigargin increased the amplitude of contractions induced by electrical field stimulation (EFS) and these effects were also reversed by nifedipine and Ani9. Thapsigargin also potentiated contractions of ASM induced by the LTCC activator FPL64176. Therefore, contractions of ASM that involved Ca 2+ influx via LTCC were enhanced by inhibition of SERCA. Immunocytochemistry experiments revealed prominent SERCA staining around the periphery of ASM cells. These data indicate that M2R-dependent contractions of ASM involve Ano1 CACC and LTCC by a mechanism involving inhibition of buffering of Ca 2+ influx by SERCA. NEW & NOTEWORTHY The role of L-type Ca 2+ channels and Ano1 Ca 2+ -activated Cl - channels in cholinergic contractions of airway smooth muscle is disputed. Here, we show that both channels are involved in M2 muscarinic receptor-dependent contractions of murine airway smooth muscle via inhibition of buffering of Ca 2+ influx by sarcoplasmic endoplasmic reticulum Ca 2+ ATPases.

We aimed to determine the relaxant pathway of seventeen synthetic compounds derived from coumarin-3-carboxamide. An isolated rat aorta assay was used. To determine the vasorelaxant mode of action, receptor blockers and specific enzyme inhibitors involved in endothelial and smooth muscle signaling pathways were used. The compounds 2, 4, and 5 showed higher activity than the other compounds. N-nitro-L-arginine methyl ester (10 µM) and methylene blue (10 µM) significantly inhibited the relaxant effect of the compounds 2, 4, and 5 (p ≤ 0.05), but not tetraethylammonium (5 mM), indomethacin (10 µM), or atropine (1 µM). The compounds 2, 4, and 5 abated the contraction induced by CaCl 2 . The compounds 2, 4, and 5 exert a relaxing effect through the nitric oxide/cyclic guanosine monophosphate pathway activation and by blocking Ca 2+ channels of the cell membrane. These findings propose coumarin-3-carboxamides as new drug entities with the potential to develop non-clinical and clinical., (© 2025 Wiley‐VHCA AG, Zurich, Switzerland.)

The cAMP-response element-binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes c -fos , Arc , and Bdnf and is essential for long-lasting synaptic plasticity underlying learning and memory. Despite this critical role, there is still ongoing debate regarding the synaptic excitation-transcription (E-T) coupling mechanisms mediating CREB activation in the nucleus. Here we employed optical uncaging of glutamate to mimic synaptic excitation of distal dendrites in conjunction with simultaneous imaging of intracellular Ca 2+ dynamics and transcriptional reporter gene expression to elucidate CREB E-T coupling mechanisms in hippocampal neurons cultured from both male and female rats. Using this approach, we found that CREB-dependent transcription was engaged following dendritic stimulation of N -methyl-d-aspartate receptors (NMDARs) only when Ca 2+ signals propagated to the soma via subsequent activation of L-type voltage-gated Ca 2+ channels resulting in activation of extracellular signal-regulated kinase MAP kinase signaling to sustain CREB phosphorylation in the nucleus. In contrast, dendrite-restricted Ca 2+ signals generated by NMDARs failed to stimulate CREB-dependent transcription. Furthermore, Ca 2+ -CaM-dependent kinase-mediated signaling pathways that may transiently contribute to CREB phosphorylation following stimulation were ultimately dispensable for downstream CREB-dependent transcription and c-Fos induction. These findings emphasize the essential role that L-type Ca 2+ channels play in rapidly relaying signals over long distances from synapses located on distal dendrites to the nucleus to control gene expression., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Rationale & Methods: While signaling of cardiac SR by surface membrane proteins (I Ca & I NCX ) is well studied, the regulation of mitochondrial Ca 2+ by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er., Results: In voltage-clamped and TIRF-imaged cardiomyocytes, low Na + induced SR Ca 2+ release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca 2+ contribution to low Na + triggered SR Ca 2+ release. Even though low Na + - or caffeine-triggered SR Ca 2+ release activated global mitochondrial Ca 2+ uptake, focal mitochondrial Ca 2+ signals varied in kinetics and magnitude, showing uptake or release of calcium, depending on cellular location of mitochondria. In spontaneously pacing cells, sustained caffeine exposures depleted the SR Ca 2+ content activating mitochondrial Ca 2+ uptake followed by sustained mitochondrial pacing. Spontaneous hiPSCCMs pacing was strongly suppressed by L-type calcium channels blockers, but not by inhibiting SERCA2a by CPA., Conclusion: Spontaneous hiPSCCMs pacing is triggered by influx of calcium through L-type Ca 2+ channel that gates the release of SR pools supplemented by NCX-mediated mitochondrial calcium contribution., Competing Interests: Declaration of competing interest No conflicts of interest, financial or otherwise, are declared by the authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We tested the hypothesis that Ca v 3.2 T-type Ca 2+ channels, which can be rebooted by sulfides from Zn 2+ inhibition under physiological conditions, and sulfide-generating enzymes including cystathionine-β-synthase (CBS) would participate in the colitis-related visceral pain in mice treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS). The visceral hypersensitivity following TNBS-induced colitis was abolished by an inhibitor or genetic deletion of Ca v 3.2 and by a CBS inhibitor, and accompanied by CBS upregulation in the colon. Our data thus suggest that the enhanced activity of Ca v 3.2 brought about by sulfides generated by upregulated CBS is involved in the colitis-related visceral hypersensitivity., Competing Interests: Declaration of competing interest The authors have no conflict of interest regarding this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Early in Alzheimer's disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca 2+ entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca 2+ ] i )-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca 2+ ] i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD., (© 2024. The Author(s).)

The house dust mite is the principal source of aero-allergen worldwide. Exposure to mite-derived allergens is associated with the development of asthma in susceptible individuals, and the majority of asthmatics are allergic to the mite. Mite-derived allergens are functionally diverse and activate multiple cell types within the lung that result in chronic inflammation. Allergens activate store-operated Ca 2+ release-activated Ca 2+ (CRAC) channels, which are widely expressed in multiple cell types within the lung that are associated with the pathogenesis of asthma. Opening of CRAC channels stimulates Ca 2+ -dependent transcription factors, including nuclear factor of activated T cells and nuclear factor-κB, which drive expression of a plethora of pro-inflammatory cytokines and chemokines that help to sustain chronic inflammation. Here, I describe drivers of asthma, properties of mite-derived allergens, how the allergens are recognized by cells, the signalling pathways used by the receptors and how these are transduced into functional effects, with a focus on CRAC channels. In vivo experiments that demonstrate the effectiveness of targeting CRAC channels as a potential new therapy for treating mite-induced asthma are also discussed, in tandem with other possible approaches., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

The orexigenic gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHSR1a). Systemic ghrelin administration has previously been shown to increase gastric motility and emptying. While these effects are known to be mediated by the vagus nerve, the cellular mechanism underlying these effects remains unclear. Therefore, the purpose of the present study was to investigate the signaling mechanism by which GHSR1a inhibits voltage-gated Ca 2+ channels in isolated rat gastric vagal afferent neurons using whole-cell patch-clamp electrophysiology. The ghrelin pharmacological profile indicated that Ca 2+ currents were inhibited with a log (Ic 50 ) = -2.10 ± 0.44 and a maximal inhibition of 42.8 ± 5.0%. Exposure to the GHSR1a receptor antagonist (D-Lys3)-GHRP-6 reduced ghrelin-mediated Ca 2+ channel inhibition (29.4 ± 16.7% vs. 1.9 ± 2.5%, n = 6, P = 0.0064). Interestingly, we observed that activation of GHSR1a inhibited Ca 2+ currents through both voltage-dependent and voltage-independent pathways. We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca 2+ current inhibition was mediated by the G α i/o family of subunits. Treatment with both PTX (Ca α q/11 family of subunits. Treatment with both PTX (Ca 2+ = 0.0327) and YM-254890 (15.2 ± 11.9%, n = 8, P = 0.0269) blocked ghrelin's effects on Ca n = 8, P = 0.0269) blocked ghrelin's effects on Ca 2+ currents, as compared with control neurons (34.3 ± 18.9%, n in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca α currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin's regulation of gastric vagal afferents. SIGNIFICANCE STATEMENT: This study demonstrated that in gastric vagal afferent neurons, activation of GHSR1a by ghrelin inhibits voltage-gated Ca i/o channels through both voltage-dependent and voltage-independent signaling pathways. These results provide necessary insights into the cellular mechanism underlying ghrelin regulation of gastric vagal afferent activity, which may benefit future studies investigating ghrelin mimetics to treat gastric motility disorders.α q/11 in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca 2+ currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin's regulation of gastric vagal afferents. SIGNIFICANCE STATEMENT: This study demonstrated that in gastric vagal afferent neurons, activation of GHSR1a by ghrelin inhibits voltage-gated Ca 2+ channels through both voltage-dependent and voltage-independent signaling pathways. These results provide necessary insights into the cellular mechanism underlying ghrelin regulation of gastric vagal afferent activity, which may benefit future studies investigating ghrelin mimetics to treat gastric motility disorders., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Vasodilation in response to low oxygen (O 2 ) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O 2 supply to tissues according to demand. However, how blood vessels react to O 2 deficiency is not well understood. A common belief is that arterial myocytes are O 2 -sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca 2+ channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O 2 modulation of Ca 2+ channels and hypoxic vasodilation. Mitochondria function as O 2 sensors and effectors that signal myocyte Ca 2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O 2 -sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology., (© 2024. The Author(s).)

Background: Schisandra chinensis is widely applied in the prevention and treatment of asthma in China, but the material basis for the anti-asthmatic effect of S. chinensis is unclear. Our previous studies found that the lignans from S. chinensis can relax tracheal smooth muscle in rats. Schisandrol A (SCA) is a representative monomer of S. chinensis lignans with high content and activity. Purpose: This study was aimed at further exploring the relaxation effect of SCA and its mechanism on the isolated tracheal smooth muscle of rats through tracheal perfusion experiments. Materials and Methods: The isolated rat tracheal ring was precontracted with acetylcholine (ACh). Then, the impact of SCA on the tension of precontracted tracheal ring was studied. Verapamil (L-type calcium channel blocker) and four potassium channel blockers, including glibenclamide, tetraethylamine, 4-aminopyridine (4-AP), and barium chloride (BaCl2), as well as propranolol (β-adrenergic receptor antagonist), were respectively used to precontract the tracheal ring for investigation. Results: SCA could dose-dependently reduce the ACh-induced contraction of the tracheal ring, and the verapamil and 4-AP could weaken this effect, while BaCl2, glibenclamide, tetraethylamine, and propranolol did not show this effect. Conclusion: SCA can significantly relax the effect of tracheal smooth muscle of rats, and the underlying mechanism might be involved in the blocking of L-type Ca2+ channels and activating the voltage-dependent potassium channels (KV). [ABSTRACT FROM AUTHOR]

Inadequate blood supply to the expanding adipose tissue (AT) is involved in the unhealthy AT remodeling and cardiometabolic consequences of obesity. Because of the pathophysiological role of upregulated mineralocorticoid receptor (MR) signaling in the complications of obesity, this study tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries of human AT. Arteries isolated from the visceral AT of obese subjects were studied in a wire myograph. Finerenone resulted in a concentration-dependent relaxation of arteries precontracted with either the thromboxane-A2 analog U46619, ET-1, or high-K + solution; the steroidal MR antagonist potassium canrenoate, by contrast, did not relax arteries contracted with either U46619 or high-K + solution. Finerenone-induced relaxation after precontraction with U46619 was greater in the arteries of obese versus nonobese subjects. Mechanistically, the vasorelaxing response to finerenone was not influenced by preincubation with the nitric oxide synthase inhibitor L-NAME or by endothelium removal. Interestingly, finerenone, like the dihydropyridine Ca 2+ -channel blocker nifedipine, relaxed arteries contracted with the L-type Ca 2+ -channel agonist Bay K8644. In conclusion, finerenone relaxes arteries of human visceral AT, likely through antagonism of L-type Ca 2+ channels. This finding identifies a novel mechanism by which finerenone may improve AT perfusion, hence protecting against the cardiometabolic complications of obesity., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The abundance of CaV2 voltage-gated calcium channels is linked to presynaptic homeostatic plasticity (PHP), a process that recalibrates synaptic strength to maintain the stability of neural circuits. However, the molecular and cellular mechanisms governing PHP and CaV2 channels are not completely understood. Here, we uncover a previously not described form of PHP in Caenorhabditis elegans , revealing an inverse regulatory relationship between the efficiency of neurotransmitter release and the abundance of UNC-2/CaV2 channels. Gain-of-function unc-2SL(S240L) mutants, which carry a mutation analogous to the one causing familial hemiplegic migraine type 1 in humans, showed markedly reduced channel abundance despite increased channel functionality. Reducing synaptic release in these unc-2SL(S240L) mutants restored channel levels to those observed in wild-type animals. Conversely, loss-of-function unc-2DA(D726A) mutants, which harbor the D726A mutation in the channel pore, exhibited a marked increase in channel abundance. Enhancing synaptic release in unc-2DA mutants reversed this increase in channel levels. Importantly, this homeostatic regulation of UNC-2 channel levels is accompanied by the structural remodeling of the active zone (AZ); specifically, unc-2DA mutants, which exhibit increased channel abundance, showed parallel increases in select AZ proteins. Finally, our forward genetic screen revealed that WWP-1, a HECT family E3 ubiquitin ligase, is a key homeostatic mediator that removes UNC-2 from synapses. These findings highlight a self-tuning PHP regulating UNC-2/CaV2 channel abundance along with AZ reorganization, ensuring synaptic strength and stability., Competing Interests: Competing interests statement:The authors declare no competing interest.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aβ) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aβ 25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aβ 25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aβ 25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca 2+ channels in their effects. After inducing Aβ 25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aβ 25-35 neurotoxicity induced a considerable reduction in input resistance (R in ), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca 2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aβ on the Ca 2+ channel current and neuronal function, which might take place in neurons during the development of AD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Tea (Camellia sinensis) is a favorite drink worldwide. Tea extracts and green tea main component (-)-epigallocatechin gallate (EGCG) are recommended for various vascular diseases. Anji white tea is a very popular green tea. Its vascular effect profile, the mechanisms, and the contribution of EGCG to its integrated effect need elucidation., Aim: To characterize the vasomotion effects of Anji white tea and EGCG, and to explore possible involvement of voltage-gated Ca 2+ channels (VGCCs) and voltage-gated K + (Kv) channels in their vasomotion effects., Materials and Methods: Anji white tea water soaking solution (AJWT) was prepared as daily tea-making process and concentrated to a concentration amounting to 200 mg/ml of dry tea leaves. The tension of rat arteries including aorta, coronary artery (RCA), cerebral basilar artery (CBA), intrarenal artery (IRA), intrapulmonary artery (IPA) and mesenteric artery (MA) was recorded with myographs. In arterial smooth muscle cells (ASMCs) freshly isolated from RCA, the levels of intracellular Ca 2+ were measured with Ca 2+ -sensitive fluorescent probe fluo 4-AM, and Kv currents were recorded with patch clamp. The expressions of VGCCs and Kv channels were assayed with RT-qPCR and immunofluorescence staining., Results: At 0.4-12.8 mg/ml of dry tea leaves, AJWT profoundly relaxed all tested arteries precontracted with various vasoconstrictors about half with a small transient potentiation on the precontractions before the relaxation. KCl-induced precontraction was less sensitive than precontractions induced by phenylephrine (PE), U46619 and serotonin (5-HT). IPA was less sensitive to the relaxation compared with other arteries. AJWT pretreatment for 1 h, 24 h and 72 h time-dependently inhibited the contractile responses of RCAs. In sharp contrast, at equivalent concentrations according to its content in AJWT, EGCG intensified the precontractions in most small arteries, except that it induced relaxation in PE-precontracted aorta and MA, U46619-precontracted aorta and CBA. EGCG pretreatment for 1 h and 24 h did not significantly affect RCA contractile responses. In RCA ASMCs, AJWT reduced, while EGCG enhanced, intracellular Ca 2+ elevation induced by depolarization which activates VGCCs. Patch clamp study showed that both AJWT and EGCG reduced Kv currents. RT-qPCR and immunofluorescence staining demonstrated that both AJWT and EGCG reduced the expressions of VGCCs and Kv channels., Conclusion: AJWT, but not EGCG, consistently induces vasorelaxation. The vasomotion effects of either AJWT or EGCG vary with arterial beds and vasoconstrictors. Modulation of VGCCs, but not Kv channels, contributes to AJWT-induced vasorelaxation. It is suggested that Anji white tea water extract instead of EGCG may be a promising food supplement for vasospastic diseases., Competing Interests: Declaration of competing interest We certify that there is no conflict of interest regarding this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear., Methods: Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca 2+ channels (T-type channels)., Results: IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2., Conclusion: Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management., (© 2024. The Author(s).)

Adult-born granule cells (abGCs) exhibit a transient period of elevated synaptic plasticity that plays an important role in hippocampal function. Various mechanisms have been implicated in this critical period for enhanced plasticity, including minimal GABAergic inhibition and high intrinsic excitability conferred by T-type Ca 2+ channels. Here we assess the contribution of synaptic inhibition and intrinsic excitability to long-term potentiation (LTP) in abGCs of adult male and female mice using perforated patch recordings. We show that the timing of critical period plasticity is unaffected by intact GABAergic inhibition such that 4-6-week-old abGCs exhibit LTP that is absent by 8 weeks. Blocking GABA A receptors, or partial blockade of GABA release from PV and nNos-expressing interneurons by a µ-opioid receptor agonist, strongly enhances LTP in 4-week-old GCs, suggesting that minimal inhibition does not underlie critical period plasticity. Instead, the closure of the critical period coincides with a reduction in the contribution of T-type Ca 2+ channels to intrinsic excitability, and a selective T-type Ca 2+ channel antagonist prevents LTP in 4-week-old but not mature GCs. Interestingly, whole-cell recordings that facilitate T-type Ca 2+ channel activity in mature GCs unmasks LTP (with inhibition intact) that is also sensitive to a T-type Ca 2+ channel antagonist, suggesting T-type channel activity in mature GCs is suppressed by native intracellular signaling. Together these results show that abGCs use T-type Ca 2+ channels to overcome inhibition, providing new insight into how high intrinsic excitability provides young abGCs a competitive advantage for experience-dependent synaptic plasticity., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Platelet-activating factor (PAF) is expected to increase esophageal motility. However, to the best of our knowledge, this has not been examined. Thus, we investigated the contractile effects of PAF on guinea pig (GP) esophageal muscularis mucosae (EMM) and the extracellular Ca 2+ influx pathways responsible. PAF (10 -9 -10 -6  M) contracted EMM in a concentration-dependent manner. PAF (10 -6  M)-induced contractions were almost completely suppressed by apafant (a PAF receptor antagonist, 3 × 10 -5  M). In EMM strips, PAF receptor and PAF-synthesizing/degrading enzyme mRNAs were detected. PAF (10 -6  M)-induced contractions were abolished by extracellular Ca 2+ removal but were not affected by diltiazem [a voltage-dependent Ca 2+ channel (VDCC) inhibitor, 10 -5  M]. PAF (10 -6  M)-induced contractions in the presence of diltiazem were significantly suppressed by LOE-908 [a receptor-operated Ca 2+ channel (ROCC) inhibitor, 3 × 10 -5  M], SKF-96365 [an ROCC and store-operated Ca 2+ channel (SOCC) inhibitor, 3 × 10 -5  M], and LOE-908 plus SKF-96365. Among the tested ROCC/SOCC-related mRNAs, Trpc3, Trpc6, and Trpv4/Orai1, Orai3, and Stim2 were abundantly expressed in EMM strips. These results indicate that PAF potently induces GP EMM contractions that are dependent on extracellular Ca 2+ influx through ROCCs/SOCCs, and VDCCs are unlikely to be involved., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The ORAI proteins serve as crucial pore-forming subunits of calcium-release-activated calcium (CRAC) channels, pivotal in regulating downstream calcium-related signaling pathways. Dysregulated calcium homeostasis arising from mutations and post-translational modifications in ORAI can lead to immune disorders, myopathy, cardiovascular diseases, and even cancers. Small molecules targeting ORAI present an approach for calcium signaling modulation. Moreover, emerging techniques like optogenetics and optochemistry aim to offer more precise regulation of ORAI. This review focuses on the role of ORAI in cancers, providing a concise overview of their significance in the initiation and progression of cancers. Additionally, it highlights state-of-the-art techniques for ORAI channel modulation, including advanced optical tools, potent pharmacological inhibitors, and antibodies. These novel strategies offer promising avenues for the functional regulation of ORAI in research and may inspire innovative approaches to cancer therapy targeting ORAI.

The process of wound healing is intricate and tightly controlled, involving a number of different cellular and molecular processes. Numerous cellular functions, especially those related to wound healing, depend critically on calcium ions (Ca 2+ ). Ca 2+ channels are proteins involved in signal transduction and communication inside cells that allow calcium ions to pass through cell membranes. Key Ca 2+ channel types involved in wound repair are described in this review.