Ca²⁺ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca²⁺ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels and pumps (including voltage-gated calcium channels, store-operated channels, receptor-operated channels, transient receptor potential ion channels, and Ca²⁺-ATPase) mediate Ca²⁺ across the plasma membrane or subcellular organelles, modulating intracellular free Ca²⁺. Therefore, these Ca²⁺ channels or pumps present important aspects of viral pathogenesis and virus–host interaction. It has been reported that viruses hijack host calcium channels or pumps, disturbing the cellular homeostatic balance of Ca²⁺. Such a disturbance benefits virus lifecycles while inducing host cells’ morbidity. Evidence has emerged that pharmacologically targeting the calcium channel or calcium release from the endoplasmic reticulum (ER) can obstruct virus lifecycles. Impeding virus-induced abnormal intracellular Ca²⁺ homeostasis is becoming a useful strategy in the development of potent antiviral drugs. In this present review, the recent identified cellular calcium channels and pumps as targets for virus attack are emphasized.

Twenty-five years ago, the first mammalian Transient Receptor Potential Canonical (TRPC) channel was cloned, opening the vast horizon of the TRPC field. Today, we know that there are seven TRPC channels (TRPC1–7). TRPCs exhibit the highest protein sequence similarity to the Drosophila melanogaster TRP channels. Similar to Drosophila TRPs, TRPCs are localized to the plasma membrane and are activated in a G-protein-coupled receptor-phospholipase C-dependent manner. TRPCs may also be stimulated in a store-operated manner, via receptor tyrosine kinases, or by lysophospholipids, hypoosmotic solutions, and mechanical stimuli. Activated TRPCs allow the influx of Ca²⁺ and monovalent alkali cations into the cytosol of cells, leading to cell depolarization and rising intracellular Ca²⁺ concentration. TRPCs are involved in the continually growing number of cell functions. Furthermore, mutations in the TRPC6 gene are associated with hereditary diseases, such as focal segmental glomerulosclerosis. The most important recent breakthrough in TRPC research was the solving of cryo-EM structures of TRPC3, TRPC4, TRPC5, and TRPC6. These structural data shed light on the molecular mechanisms underlying TRPCs’ functional properties and propelled the development of new modulators of the channels. This review provides a historical overview of the major advances in the TRPC field focusing on the role of gene knockouts and pharmacological tools.

Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000–9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators.

Objective—: Nucleotide P2Y ₂ receptor (P2Y ₂ R) contributes to vascular inflammation by increasing vascular cell adhesion molecule-1 expression in endothelial cells (EC), and global P2Y ₂ R deficiency prevents fatty streak formation in apolipoprotein E null (ApoE ^−/− ) mice. Because P2Y ₂ R is ubiquitously expressed in vascular cells, we investigated the contribution of endothelial P2Y ₂ R in the pathogenesis of atherosclerosis. Approach and Results—: EC-specific P2Y ₂ R-deficient mice were generated by breeding VEcadherin5-Cre mice with the P2Y ₂ R floxed mice. Endothelial P2Y ₂ R deficiency reduced endothelial nitric oxide synthase activity and significantly altered ATP- and UTP (uridine 5’-triphosphate)-induced vasorelaxation without affecting vasodilatory responses to acetylcholine. Telemetric blood pressure and echocardiography measurements indicated that EC-specific P2Y ₂ R-deficient mice did not develop hypertension. We investigated the role of endothelial P2Y ₂ R in the development of atherosclerotic lesions by crossing the EC-specific P2Y ₂ R knockout mice onto an ApoE ^−/− background and evaluated lesion development after feeding a standard chow diet for 25 weeks. Histopathologic examination demonstrated reduced atherosclerotic lesions in the aortic sinus and entire aorta, decreased macrophage infiltration, and increased smooth muscle cell and collagen content, leading to the formation of a subendothelial fibrous cap in EC-specific P2Y ₂ R-deficient ApoE ^−/− mice. Expression and proteolytic activity of matrix metalloproteinase-2 was significantly reduced in atherosclerotic lesions from EC-specific P2Y ₂ R-deficient ApoE ^−/− mice. Furthermore, EC-specific P2Y ₂ R deficiency inhibited nitric oxide production, leading to significant increase in smooth muscle cell migration out of aortic explants. Conclusions—: EC-specific P2Y ₂ R deficiency reduces atherosclerotic burden and promotes plaque stability in ApoE ^−/− mice through impaired macrophage infiltration acting together with reduced matrix metalloproteinase-2 activity and increased smooth muscle cell migration.