1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.

The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Vitamin D and Intestinal Calcium Absorption

Calcium balance is essential for a multitude of physiological processes, ranging from cell signaling to maintenance of bone health. Adequate intestinal absorption of calcium is a major factor for maintaining systemic calcium homeostasis. Recent observations indicate that a reduction of gastric acidity may impair effective calcium uptake through the intestine. This article reviews the physiology of gastric acid secretion, intestinal calcium absorption, and their respective neuroendocrine regulation and explores the physiological basis of a potential link between these individual systems.

https://www.physiology.org/doi/pdf/10.1152/physrev.00015.2012

Gastric Acid, Calcium Absorption, and Their Impact on Bone Health

Phosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of phosphoinositide-metabolizing enzymes is responsible for a growing number of diseases in humans. Two related disorders, oculocerebrorenal syndrome of Lowe (OCRL) and Dent-2 disease, are caused by mutation of the inositol 5-phosphatase OCRL1. Here, we review recent advances in our understanding of OCRL1 function. OCRL1 appears to regulate many processes within the cell, most of which depend upon coordination of membrane dynamics with remodeling of the actin cytoskeleton. Recently developed animal models have managed to recapitulate features of Lowe syndrome and Dent-2 disease, and revealed new insights into the underlying mechanisms of these disorders. The continued use of both cell-based approaches and animal models will be key to fully unraveling OCRL1 function, how its loss leads to disease and, importantly, the development of therapeutics to treat patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/tra.12160

The Cellular and Physiological Functions of the Lowe Syndrome Protein OCRL1

Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2.

Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase, and mutations of OCRL cause Lowe syndrome and Dent disease, both of whi...

Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease

Concerted actions of NHERF2 and WNK4 in regulating TRPV5

Background Arginine vasopressin (AVP) is widely used in the treatment of critical diseases with hypotension, but the reports about its effect on gastrointestinal motility are controversial. The purpose of this study was to characterize the role of AVP in the regulation of colonic motility and the underlying mechanism.



Methods  The contraction of the circular muscle strips (CM) of colon in male rats was monitored by a polygraph. The expressions of cytoplasmic inducible nitric oxide synthase (iNOS), I-κB, and the nuclear P65 in proximal colon were measured by Western blot. The V1 receptors (V1Rs) and iNOS were localized by immunohistochemistry. The content of nitric oxide (NO) in the colon was measured by Griess reagent at the absorbance of 560 nm.



Key Results  Arginine vasopressin (10−10–10−6 mol L−1) caused a concentration-dependent inhibition on CM contraction. Pretreatment with one of the following chemicals, including V-1880 (10−7 mol L−1), TTX (10−5 mol L−1), l-NAME (10−4 mol L−1), NPLA (10−7 mol L−1), SMT (10−3 mol L−1), and PDTC (10−3 mol L−1), attenuated the inhibitory effect of AVP on CM contraction. Arginine vasopressin increased the expression of iNOS and the content of NO in proximal colon. These effects were attenuated by pretreatment with PDTC (10−3 mol L−1). Following AVP administration, the amount of cytoplasmic I-κB decreased, but that of nuclear P65 increased. Double immunofluorescence labeling revealed that V1Rs and iNOS were co-localized on the cells of myenteric plexus in proximal colon.



Conclusions & Inferences  Arginine vasopressin inhibited the contraction of CM in proximal colon. This effect was mediated by NO produced from NF-κB–iNOS pathway and neuronal NOS activation in myenteric plexus.

Nitric oxide in enteric nervous system mediated the inhibitory effect of vasopressin on the contraction of circular muscle strips from colon in male rats.

Background Inflammatory bowel disease (IBD) is a functional disorder with chronic and relapsing clinical features. Vasopressin (VP) is a hormone responsible for water and stress homeostasis and also regulates gastrointestinal inflammation and motility. We explored whether VP was related to IBD pathogenesis and its possible pathway. Methods Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice. The disease activity and colonic damage were evaluated through a scoring system. Locations of the V1a receptor were revealed by immunochemistry method in colon. Ussing chamber technique was performed for the electrophysiological characterization by using rat ileum. The (Arg8 )-Vasopressin (AVP)-evoked short-circuit current (Isc) was recorded in the presence of conivaptan (V1a and V2 receptor antagonist), tolvaptan (V1b receptor antagonist), tetrodotoxin (TTX), atropine, cyclooxygenase (COX) inhibitors (indomethacin, nonspecific COX antagonist; SC560, COX-1 antagonist; NS560, COX-2 antagonist), and a stabilizer of mast cell (cromolyn sodium), respectively. Key results TNBS resulted in the obvious loss of body weight and tissue damages in mice. AVP significantly aggravated the TNBS-induced colitis, which was attenuated by conivaptan but not tolvaptan. V1a receptors were found immunopositive in neurons among the enteric nervous system. AVP evoked a pulsatile response in Isc. Its amplitude, frequency, and cycle duration were around 8-15 µA/cm2 , 10-11 mHz, and 1.5 minutes, respectively. Notably, the AVP-evoked change in Isc was abolished by TTX, atropine, conivaptan, indomethacin, NS560, and cromolyn sodium, respectively. Conclusions and inferences VP-V1a receptor played the proinflammatory role in TNBS-induced colitis by promoting COX-2-dependent prostaglandin release from mucosal mast cells, which was mediated by the cholinergic pathway.

Vasopressin augments TNBS-induced colitis through enteric neuronal V 1a receptor-mediated COX-2-dependent prostaglandin release from mast cells in mice.

Haiyan Jing

Papers

Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2.

Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease

Concerted actions of NHERF2 and WNK4 in regulating TRPV5

Nitric oxide in enteric nervous system mediated the inhibitory effect of vasopressin on the contraction of circular muscle strips from colon in male rats.

Vasopressin augments TNBS-induced colitis through enteric neuronal V 1a receptor-mediated COX-2-dependent prostaglandin release from mast cells in mice.