Ca signaling in vascular smooth muscle and endothelial cells in blood vessel remodeling: a review.

Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) act together to regulate blood pressure and systemic blood flow by appropriately adjusting blood vessel diameter in response to biochemical or biomechanical stimuli. Ion channels that are expressed in these cells regulate membrane potential and cytosolic Ca concentration ([Ca]) in response to such stimuli. The subsets of these ion channels involved in Ca signaling often form molecular complexes with intracellular molecules via scaffolding proteins.

Ca3.2 T-type calcium channels contribute to CGRP- induced allodynia in a rodent model of experimental migraine.

Background: Migraine is a painful neurological syndrome characterized by attacks of throbbing headache, of moderate to severe intensity, which is associated with photo- and phono- sensitivity as well as nausea and vomiting. It affects about 15% of the world's population being 2-3 times more prevalent in females. The calcitonin gene-related peptide (CGRP) is a key mediator in the pathophysiology of migraine, and a significant advance in the field has been the development of anti-CGRP therapies.

Navigating the Controversies: Role of TRPM Channels in Pain States.

Chronic pain is a debilitating condition that affects up to 1.5 billion people worldwide and bears a tremendous socioeconomic burden. The success of pain medicine relies on our understanding of the type of pain experienced by patients and the mechanisms that give rise to it.

Development of Tetrahydroquinoline-Based Inhibitors for Chronic Pain.

Chronic pain affects a substantial portion of the population, posing a significant health challenge. Current treatments often come with limitations and side effects, necessitating novel therapeutic approaches. Our study focuses on disrupting the Cav3.

Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling.

Determinants of interactions of a novel next-generation gabapentinoid NVA1309 and mirogabalin with the Cavα2δ-1 subunit.

NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.

Spared nerve injury leads to reduced activity of neurons projecting from the ventrolateral periaqueductal gray to the locus coeruleus.

The ventrolateral periaqueductal gray (vlPAG) serves as a central hub for descending pain modulation. It receives upstream projections from the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), and projects downstream to the locus coeruleus (LC) and the rostroventral medulla (RVM). While much research has focused on upstream circuits and the LC-RVM connection, less is known about the PAG-LC circuit and its involvement in neuropathic pain.

Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry.

Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal.

Expression of GAD2 in excitatory neurons projecting from the ventrolateral periaqueductal gray to the locus coeruleus.

The ventrolateral periaqueductal gray (vlPAG) functionally projects to diverse brain regions, including the locus coeruleus (LC). Excitatory projections from the vlPAG to the LC are well described, while few studies have indicated the possibility of inhibitory projections. Here, we quantified the relative proportion of excitatory and inhibitory vlPAG-LC projections in male and female mice, and found an unexpected overlapping population of neurons expressing both GAD2 and VGLUT2.

Functional remodeling of presynaptic voltage-gated calcium channels in superficial layers of the dorsal horn during neuropathic pain.

N- and P/Q-type voltage-gated Ca channels are critical for synaptic transmission. While their expression is increased in the dorsal root ganglion (DRG) neuron cell bodies during neuropathic pain conditions, less is known about their synaptic remodeling. Here, we combined genetic tools with 2-photon Ca imaging to explore the functional remodeling that occurs in central presynaptic terminals of DRG neurons during neuropathic pain.

Pronociceptive role of spinal Ca2.3 (R-type) calcium channels in a mouse model of postoperative pain.

Background: More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Ca2.

Chronic pain: Central role of the claustrum in pain processing.

Nociceptive stimuli are processed by the brain into an unpleasant sensation. Two new studies highlight an important role of the claustrum in the processing of pain-related information.

A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain.

The Voltage-Gated Calcium Channel (VGCC) auxiliary subunit Cavα2δ-1 (CACNA2D1) is the target/receptor of gabapentinoids which are known therapeutics in epilepsy and neuropathic pain. Following damage to the peripheral sensory nervous system, Cavα2δ-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of chronic neuropathic pain. Gabapentinoids, such as gabapentin and pregabalin, engage with Cavα2δ-1 via binding an arginine residue (R241) within an RRR motif located at the N-terminus of human Cavα2δ-1.

Voltage-gated Calcium Channels as Potential Therapeutic Targets in Migraine.

Migraine is a complex and highly incapacitating neurological disorder that affects around 15% of the general population with greater incidence in women, often at the most productive age of life. Migraine physiopathology is still not fully understood, but it involves multiple mediators and events in the trigeminovascular system and the central nervous system. The identification of calcitonin gene-related peptide as a key mediator in migraine physiopathology has led to the development of effective and highly selective antimigraine therapies.

Prunin from (L.) Rafin Inhibits Aldose Reductase and Glucose-Fructose-Mediated Protein Glycation and Oxidation of Human Serum Albumin.

Diabetes complications are associated with aldose reductase (AR) and advanced glycation end products (AGEs). Using bioassay-guided isolation by column chromatography, 10 flavonoids and one coumarin were isolated from Rafin and tested in vitro for an inhibitory effect against human recombinant AR (HRAR) and rat lens AR (RLAR). Prunin, narirutin, and naringin inhibited RLAR (IC 0.

Opening the K3.1 gates: A therapeutic strategy for progressive myoclonus epilepsy type 7?

Progressive myoclonus epilepsy type 7, a debilitating neurological disorder, is caused by a loss-of-function mutation in the K3.1 channel. Exciting work by Feng et al.

Effect of ABT-639 on Cav3.2 channel activity and its analgesic actions in mouse models of inflammatory and neuropathic pain.

Cav3.2 T-type calcium channels are important targets for pain relief in rodent models of inflammatory and neuropathic pain. Even though many T-type channel blockers have been tested in mice, only one molecule, ABT-639, has been tested in phase II clinical studies and did not produce analgesic effects over placebo.

The T-type calcium channelosome.

T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane.

Caveolin-1 forms a complex with P2X7 receptor and tunes P2X7-mediated ATP signaling in mouse bone marrow-derived macrophages.

The ionotropic purinergic P2X7 receptor responds to extracellular ATP and can trigger proinflammatory immune signaling in macrophages. Caveolin-1 (Cav-1) is known to modulate functions of macrophages and innate immunity. However, it is unknown how Cav-1 modulates P2X7 receptor activity in macrophages.

Electrophysiological characterization of a Ca3.2 calcium channel missense variant associated with epilepsy and hearing loss.

T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Ca3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss-apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition.

Inhibitory insula-ACC projections modulate affective but not sensory aspects of neuropathic pain.

The insula and anterior cingulate cortex (ACC) are brain regions that undergo structural and functional reorganization in neuropathic pain states. Here, we aimed to study inhibitory parvalbumin positive (PV+) posterior insula (pIC) to posterior ACC (pACC) projections, and to evaluate the effects of direct optogenetic manipulation of such projections on mechanical nociception and spontaneous ongoing pain in mice with Spared Nerve Injury (SNI). CTB tract-tracing in male PVCrexAi9 mice revealed a small proportion of PV+ projections from the pIC to the pACC.