Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.

https://www.mdpi.com/1422-0067/20/14/3537/pdf

Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders.

The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, α2δ-1 or Cava2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The α2δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α2δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDA-sensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to α2δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α2δ-1 protein. However, recent findings show that the α2δ-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.

https://jpet.aspetjournals.org/content/jpet/374/1/161.full.pdf

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

The overexpression of phosphodiesterase 4 (PDE4) enzymes is reported in several neurodegenerative diseases. PDE4 depletes cyclic 3'-5' adenosine monophosphate (cAMP) and, in turn, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), the key players in cognitive function. The present study was undertaken to investigate the mechanism behind the protective effects of roflumilast (ROF), a cAMP-specific PDE4 inhibitor, against quinolinic acid (QUIN)-induced neurotoxicity using human primary cortical neurons. Cytotoxicity was analyzed using an MTS assay. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured by DCF-DA and JC-10 staining, respectively. Caspase 3/7 activity was measured using an ApoTox-Glo Triplex assay kit. cAMP was measured using an ELISA kit. The protein expression of CREB, BDNF, SAP-97, synaptophysin, synapsin-I, and PSD-95 was analyzed by the Western blotting technique. QUIN exposure down-regulated CREB, BDNF, and synaptic protein expression in neurons. Pretreatment with ROF increased the intracellular cAMP, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD+) content and decreased the ROS and caspase 3/7 levels in QUIN-exposed neurons. ROF up-regulated the expression of synapse proteins SAP-97, synaptophysin, synapsin-I, PSD-95, and CREB and BDNF, which indicates its potential role in memory. This study suggests for the first time that QUIN causes pre- and postsynaptic protein damage. We further demonstrate the restorative effects of ROF on the mitochondrial membrane potential and antiapoptotic properties in human neurons. These data encourage further investigations to reposition ROF in neurodegenerative diseases and their associated cognitive deficits.

Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid.

Ankyrin B (AnkB) is an adaptor and scaffold for motor proteins and various ion channels that is ubiquitously expressed, including in the brain. AnkB has been associated with neurological disorders such as epilepsy and autism spectrum disorder, but understanding of the underlying mechanisms is limited. Cav2.1, the pore-forming subunit of P/Q type voltage gated calcium channels, is a known interactor of AnkB and plays a crucial role in neuronal function. Here we report that wildtype AnkB increased overall Cav2.1 levels without impacting surface Cav2.1 levels in HEK293T cells. An AnkB variant, p.S646F, which we recently discovered to be associated with seizures, further increased overall Cav2.1 levels, again with no impact on surface Cav2.1 levels. AnkB p.Q879R, on the other hand, increased surface Cav2.1 levels in the presence of accessory subunits α2δ1 and β4. Additionally, AnkB p.E1458G decreased surface Cav2.1 irrespective of the presence of accessory subunits. In addition, we found that partial deletion of AnkB in cortex resulted in a decrease in overall Cav2.1 levels, with no change to the levels of Cav2.1 detected in synaptosome fractions. Our work suggests that depending on the particular variant, AnkB regulates intracellular and surface Cav2.1. Notably, expression of the AnkB variant associated with seizure (AnkB p.S646F) caused further increase in intracellular Cav2.1 levels above that of even wildtype AnkB. These novel findings have important implications for understanding the role of AnkB and Cav2.1 in the regulation of neuronal function in health and disease.

/pdf/ankyrin-b-and-ankyrin-b-variants-differentially-modulate-2ov2d1jomx.pdf

Ankyrin B and Ankyrin B variants differentially modulate intracellular and surface Cav2.1 levels

The heart flexibly changes its structure in response to changing environments and oxygen/nutrition demands of the body. Increased and decreased mechanical loading induces hypertrophy and atrophy of cardiomyocytes, respectively. In physiological conditions, these structural changes of the heart are reversible. However, chronic stresses such as hypertension or cancer cachexia cause irreversible remodeling of the heart, leading to heart failure. Accumulating evidence indicates that calcium dyshomeostasis and aberrant reactive oxygen species production cause pathological heart remodeling. Canonical transient receptor potential (TRPC) is a nonselective cation channel subfamily whose multimodal activation or modulation of channel activity play important roles in a plethora of cellular physiology. Roles of TRPC channels in cardiac physiology have been reported in pathological cardiac remodeling. In this review, we summarize recent findings regarding the importance of TRPC channels in flexible cardiac remodeling (i.e., cardiac plasticity) in response to environmental stresses and discuss questions that should be addressed in the near future.

https://www.mdpi.com/2073-4409/9/2/454/pdf

TRPC Channels in Cardiac Plasticity.

Action potential (AP) induces presynaptic membrane depolarization and subsequent opening of Ca2+ channels, and then triggers neurotransmitter release at the active zone of presynaptic terminal. Presynaptic Ca2+ channels and SNARE proteins (SNAREs) interactions form a large signal transfer complex, which are core components for exocytosis. Ca2+ channels serve to regulate the activity of Ca2+ channels through direct binding and indirect activation of active zone proteins and SNAREs. The activation of Ca2+ channels promotes synaptic vesicle recruitment, docking, priming, fusion and neurotransmission release. Intracellular calcium increase is a key step for the initiation of vesicle fusion. Various voltage-gated calcium channel (VGCC) subtypes exert different physiological functions. Until now, it has not been clear how different subtypes of calcium channels integrally regulate the release of neurotransmitters within 200 μs of the AP arriving at the active zone of synaptic terminal. In this mini review, we provide a brief overview of the structure and physiological function of Ca2+ channel subtypes, interactions of Ca2+ channels and SNAREs in neurotransmitter release, and dynamic fine-tune Ca2+ channel activities by G proteins (Gβγ), multiple protein kinases and Ca2+ sensor (CaS) proteins.

/pdf/new-insights-into-interactions-of-presynaptic-calcium-2unape9yo9.pdf

New Insights Into Interactions of Presynaptic Calcium Channel Subtypes and SNARE Proteins in Neurotransmitter Release.

Fibroblast proliferation and migration are central in atrial fibrillation (AF) promoting structure remodeling, which is strongly associated with aging and hypertension. Transient receptor potential canonical-3 channel (TRPC3) is a key mediator of cardiac fibrosis and the pathogenesis of AF. Here, we have observed the increased TRPC3 expression that induced atrial fibrosis which possibly is either mediated by the aging process or related to hypertensive progression. In this study, we measured the pathological structure remodeling by H&E staining, Masson staining, and transmission electron microscope (TEM). The protein expression levels of fibrotic biomarkers and TRPC3 were measured by Western blotting with atrial tissues from normotensive Wistar Kyoto rats (WKY 4m-o (4 months old)), old WKY (WKY 24m-o (24 months old)), spontaneously hypertensive rat (SHR 4m-o (4 months old)), and old SHR (SHR 24m-o (24 months old)). To illuminate the molecular mechanism of TRPC3 in atrial fibrosis of aging rats and SHR, we detected the inhibited role of TRPC3 selective blocker ethyl-1-(4-(2,3,3-trichloroacrylamide) phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate,pyrazole-3 (Pyr3) on angiotensin II (Ang II) induced fibrosis in neonatal rat atrial fibroblasts. The pathological examination showed that the extracellular matrix (ECM) and collagen fibrils were markedly increased in atrial tissues from aged and hypertensive rats. The protein expressions of fibrotic biomarkers (collagen I, collagen III, and transforming growth factor-β1 (TGF-β1)) were significantly upregulated in atrial tissues from the WKY 24m-o group, SHR 4m-o group, and SHR 24m-o group compared with the WKY 4m-o group. Meanwhile, the expression level of TRPC3 was significantly upregulated in WKY 24m-o and SHR 4m-o atrial tissues compared to WKY 4m-o rats. In isolated and cultured neonatal rat atrial fibroblasts, Ang II induced the atrial fibroblast migration and proliferation and upregulated the expression levels of TRPC3 and fibrotic biomarkers. TRPC3 selected blocker Pyr3 attenuated the migration and proliferation in neonatal rat atrial fibroblasts. Furthermore, Pyr3 significantly alleviated Ang II-induced upregulation of TRPC3, collagen I, collagen III, and TGF-β1 through the molecular mechanism of the TGF-β/Smad2/3 signaling pathway. Similarly, knocking down TRPC3 using short hairpin RNA (shTRPC3) also attenuated Ang II-induced upregulation of TGF-β1. Pyr3 preconditioning decreased Ang II-induced intracellular Ca2+ transient amplitude elevation. Furthermore, AT1 receptor was involved in Ang II-induced TRPC3 upregulation. Hence, upregulation of TRPC3 in aging and hypertension is involved in an atrial fibrosis process. Inhibition of TRPC3 contributes to reverse Ang II-induced fibrosis. TRPC3 may be a potential therapeutic target for preventing fibrosis in aging and hypertension.

/pdf/upregulation-of-transient-receptor-potential-canonical-type-z4j5uwzbws.pdf

Upregulation of Transient Receptor Potential Canonical Type 3 Channel via AT1R/TGF-β1/Smad2/3 Induces Atrial Fibrosis in Aging and Spontaneously Hypertensive Rats

Acacetin alleviates myocardial fibrosis via TGF-β1/Smad3 signaling pathway

Comprehensive analysis of a pyroptosis-related gene signature of clinical and biological value in acute myeloid leukaemia.

ABSTRACT Vaccination is an important tool for controlling the spread of coronavirus disease. Notably, it is important to achieve higher vaccine booster coverage across key groups – including front-line workers who could be exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and those who live and work in crowded places – to prevent or reduce the risk of severe infection and poor disease outcomes. The purpose of the study was to understand the COVID-19 vaccine booster hesitancy among key groups in Luzhou, China, to analyze its influencing factors, and to provide scientific basis and theoretical guidance for the implementation of targeted intervention. Guided by the “3Cs” model, a self-designed questionnaire was prepared through a literature search using the Delphi method. All questionnaires were completed online through a QR code. Among the 548 participants, 173 had vaccine hesitation, accounting for 31.6%. Indeed, the scores for perceived safety, expected vaccine effectiveness, and trust in the vaccine delivery system were all lower in the hesitance group than in the non-hesitance group. However, the scores for low necessity were higher in the hesitance group. The factors influencing booster hesitancy were examined, and the probability of hesitancy decreased by 72.2% and 62.5% for every 1-point increase in the confidence and safety scores, respectively. Meanwhile, the probability of hesitancy increased by 25.8% for every 1-point increase in the low necessity score. Although the COVID-19 vaccine booster hesitancy reported in the study was relatively low, a large gap remains in the willingness to receive COVID-19 vaccination in China. Therefore, the state and relevant departments should take targeted measures to help reduce vaccine hesitancy among the public and enable smooth progress in the large-scale COVID-19 vaccine booster campaign in the future.

https://doi.org/10.1080/21645515.2023.2166323

Rongfang He

Papers

New Insights Into Interactions of Presynaptic Calcium Channel Subtypes and SNARE Proteins in Neurotransmitter Release.

Upregulation of Transient Receptor Potential Canonical Type 3 Channel via AT1R/TGF-β1/Smad2/3 Induces Atrial Fibrosis in Aging and Spontaneously Hypertensive Rats

Acacetin alleviates myocardial fibrosis via TGF-β1/Smad3 signaling pathway

Comprehensive analysis of a pyroptosis-related gene signature of clinical and biological value in acute myeloid leukaemia.

COVID-19 vaccine booster dose hesitancy among key groups: A cross-sectional study