Enhancement of Lipolysis in 3T3-L1 Adipocytes by Nitroarene Capsaicinoid Analogs

Transient receptor potential vanilloid 1 (TRPV1) activation by capsaicin binding increased intracellular calcium influx and stimulated adipocyte-to-adipocyte communication, leading to lipolysis. Generally, enhancement of π-stacking capabilities improves certain binding interactions. Notably, nitroarenes exhibit strong binding interactions with aromatic amino acid side chains in proteins. New capsaicinoid analogs were designed by substitution of the OCH3 group with a nitrogen dioxide (NO2) group on the vanillyl ring to investigate how π-stacking interactions in capsaicinoid analogs contribute to lipolysis. Capsaicinoid analogs, nitro capsaicin (5), and nitro dihydrocapsaicin (6) were prepared in moderate yields via coupling of a nitroaromatic amine salt and fatty acids. Oil Red O staining and triglyceride assays with 10 µM loading of capsaicin (CAP), dihydrocapsaicin (DHC), 5, and 6 were performed to investigate their effect on lipolysis in 3T3-L1 adipocytes. Both assay results indicated that 5 and 6 decreased lipid accumulation by 13.6% and 14.7%, respectively, and significantly reduced triglyceride content by 26.9% and 28.4%, respectively, in comparison with the control experiment. Furthermore, the decrease in triglyceride content observed in response to nitroarene capsaicinoid analogs was approximately 2-folds higher than that of CAP and DHC. These results arose from the NO2 group augmented π-π stacking with Tyr511 and the attractive charge interaction with Glu570 affecting binding interactions with TRPV1 receptors.

Download Full-text

Intra-arterial instillation of a nociceptive agent modulate cardiorespiratory parameters involving 5-HT3 and TRPV1 receptors in anesthetized rats

Cardiovascular & Haematological Disorders - Drug Targets ◽

10.2174/1871529x21666210408101442 ◽

2021 ◽

Vol 21 ◽

Author(s):

Sanjeev K. Singh ◽

M. S. Muthu ◽

Ravindran Revand ◽

M. B. Mandal

Keyword(s):

Transient Receptor Potential ◽

Sensory Nerve ◽

Receptor Potential ◽

Neural Mechanisms ◽

Transient Receptor Potential Vanilloid ◽

Anesthetized Rats ◽

Trpv1 Receptors ◽

Perivascular Nerves ◽

Transient Receptor

Background: Since long back, it has been a matter of discussion regarding the role of peripheral blood vessels in regulation of cardiorespiratory (CVR) system. Objective: The role of 5-HT3 and TRPV1 receptors present on perivascular nerves in elicitation of CVR reflexes was examined after intra-arterial instillation of bradykinin in urethane anesthetized rats. Materials and Methods: Femoral artery was cannulated retrogradely and was utilized for the instillation of saline/agonist/antagonist and recording of blood pressure (BP), using a double ported 24G cannula. BP, respiration and ECG were recorded for 30 min after bradykinin (1 µM) in the absence or presence of antagonists. Results: Instillation of bradykinin produced immediate hypotensive (40%), bradycardiac (17%), tachypnoeic (45%) and hyperventilatory (96%) responses of shorter latencies (5-8 s) favoring the neural mechanisms in producing the responses. In lignocaine (2%) pretreated animals, bradykinin-induced hypotensive (10%), bradycardiac (1.7%), tachypnoeic (13%) and hyperventilatory (13%) responses attenuated significantly. Pretreatment with ondansetron (100 µg/kg), 5-HT3-antagonist attenuated the hypotensive (10%), bradycardiac (1.7%), tachypnoeic (11%) and hyperventilatory (11%) responses significantly. Pretreatment with capsazepine (1 mg/kg), transient receptor potential vanilloid 1- antagonist blocked the hypotensive (5%), bradycardiac (1.2%), tachypnoeic (6%) and hyperventilatory (6%) responses significantly. Conclusion: In conclusion, presence of a nociceptive agent in the local segment of an artery evokes vasosensory reflex responses modulating CVR parameters involving TRPV1 and 5-HT3 receptors present on the perivascular sensory nerve terminals in anesthetized rats.

Download Full-text

The Role of Transient Receptor Potential Vanilloid 1 (Trpv1) Receptors in Dextran Sulfate-Induced Colitis in Mice

Journal of Molecular Neuroscience ◽

10.1007/s12031-010-9366-5 ◽

2010 ◽

Vol 42 (1) ◽

pp. 80-88 ◽

Cited By ~ 34

Author(s):

Istvan Szitter ◽

Gabor Pozsgai ◽

Katalin Sandor ◽

Krisztian Elekes ◽

Agnes Kemeny ◽

...

Keyword(s):

Transient Receptor Potential ◽

Dextran Sulfate ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Trpv1 Receptors ◽

Transient Receptor

Download Full-text

Molecular mapping of transmembrane mechanotransduction through the β1 integrin–CD98hc–TRPV4 axis

Journal of Cell Science ◽

10.1242/jcs.248823 ◽

2020 ◽

Vol 133 (20) ◽

pp. jcs248823 ◽

Cited By ~ 1

Author(s):

Ratnakar Potla ◽

Mariko Hirano-Kobayashi ◽

Hao Wu ◽

Hong Chen ◽

Akiko Mammoto ◽

...

Keyword(s):

Transient Receptor Potential ◽

Molecular Mapping ◽

Calcium Influx ◽

Focal Adhesions ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Β1 Integrin ◽

Mechanical Forces ◽

C Terminus ◽

Transient Receptor

ABSTRACTOne of the most rapid (less than 4 ms) transmembrane cellular mechanotransduction events involves activation of transient receptor potential vanilloid 4 (TRPV4) ion channels by mechanical forces transmitted across cell surface β1 integrin receptors on endothelial cells, and the transmembrane solute carrier family 3 member 2 (herein denoted CD98hc, also known as SLC3A2) protein has been implicated in this response. Here, we show that β1 integrin, CD98hc and TRPV4 all tightly associate and colocalize in focal adhesions where mechanochemical conversion takes place. CD98hc knockdown inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis reveals that forces applied to β1 integrin must be transmitted from its cytoplasmic C terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultrarapid, force-induced channel activation within the focal adhesion.

Download Full-text

Presynaptic inhibition of transient receptor potential vanilloid type 1 (TRPV1) receptors by noradrenaline in nociceptive neurons

The Journal of Physiology ◽

10.1113/jp273455 ◽

2017 ◽

Vol 595 (8) ◽

pp. 2639-2660 ◽

Cited By ~ 15

Author(s):

Saikat Chakraborty ◽

Vincent Elvezio ◽

Martin Kaczocha ◽

Mario Rebecchi ◽

Michelino Puopolo

Keyword(s):

Presynaptic Inhibition ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Nociceptive Neurons ◽

Trpv1 Receptors ◽

Transient Receptor

Download Full-text

Effect of Surgical and Chemical Sensory Denervation on Non-neural Expression of the Transient Receptor Potential Vanilloid 1 (TRPV1) Receptors in the Rat

Journal of Molecular Neuroscience ◽

10.1007/s12031-012-9766-9 ◽

2012 ◽

Vol 48 (3) ◽

pp. 795-803 ◽

Cited By ~ 22

Author(s):

József Kun ◽

Zsuzsanna Helyes ◽

Anikó Perkecz ◽

Ágnes Bán ◽

Beáta Polgár ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Trpv1 Receptors ◽

Sensory Denervation ◽

Transient Receptor

Download Full-text

Propofol Restores Transient Receptor Potential Vanilloid Receptor Subtype-1 Sensitivity via Activation of Transient Receptor Potential Ankyrin Receptor Subtype-1 in Sensory Neurons

Anesthesiology ◽

10.1097/aln.0b013e31820dee67 ◽

2011 ◽

Vol 114 (5) ◽

pp. 1169-1179 ◽

Cited By ~ 16

Author(s):

Hongyu Zhang ◽

Peter J. Wickley ◽

Sayantani Sinha ◽

Ian N. Bratz ◽

Derek S. Damron

Keyword(s):

Sensory Neurons ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Vanilloid Receptor ◽

Receptor Subtype ◽

Transient Receptor Potential Vanilloid ◽

Peripheral Sensitization ◽

Drg Neurons ◽

Trpv1 Receptors ◽

Transient Receptor

Background Cross talk between peripheral nociceptors belonging to the transient receptor potential vanilloid receptor subtype-1 (TRPV1) and ankyrin subtype-1 (TRPA1) family has been demonstrated recently. Moreover, the intravenous anesthetic propofol has directly activates TRPA1 receptors and indirectly restores sensitivity of TRPV1 receptors in dorsal root ganglion (DRG) sensory neurons. Our objective was to determine the extent to which TRPA1 activation is involved in mediating the propofol-induced restoration of TRPV1 sensitivity. Methods Mouse DRG neurons were isolated by enzymatic dissociation and grown for 24 h. F-11 cells were transfected with complementary DNA for both TRPV1 and TRPA1 or TRPV1 only. The intracellular Ca concentration was measured in individual cells via fluorescence microscopy. After TRPV1 desensitization with capsaicin (100 nM), cells were treated with propofol (1, 5, and 10 μM) alone or with propofol in the presence of the TRPA1 antagonist, HC-030031 (0.5 μM), or the TRPA1 agonist, allyl isothiocyanate (AITC; 100 μM); capsaicin was then reapplied. Results In DRG neurons that contain both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in DRG neurons containing only TRPV1 receptors, exposure to propofol or AITC after desensitization did not restore capsaicin-induced TRPV1 sensitivity. Similarly, in F-11 cells transfected with both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in F-11 cells transfected with TRPV1 only, neither propofol nor AITC was capable of restoring TRPV1 sensitivity. Conclusions These data demonstrate that propofol restores TRPV1 sensitivity in primary DRG neurons and in cultured F-11 cells transfected with both the TRPV1 and TRPA1 receptors via a TRPA1-dependent process. Propofol's effects on sensory neurons may be clinically important and may contribute to peripheral sensitization to nociceptive stimuli in traumatized tissue.

Download Full-text

Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00224.2014 ◽

2014 ◽

Vol 307 (8) ◽

pp. R945-R955 ◽

Cited By ~ 13

Author(s):

Ashwini Saxena ◽

Martha Bachelor ◽

Yong H. Park ◽

Flavia R. Carreno ◽

T. Prashant Nedungadi ◽

...

Keyword(s):

Angiotensin Ii ◽

Membrane Trafficking ◽

Transient Receptor Potential ◽

Calcium Influx ◽

Src Kinase ◽

Receptor Potential ◽

Family Type ◽

Transient Receptor Potential Vanilloid ◽

Ang Ii ◽

Transient Receptor

Transient receptor potential vanilloid family type 4 (TRPV4) channels are expressed in central neuroendocrine neurons and have been shown to be polymodal in other systems. We previously reported that in the rodent, a model of dilutional hyponatremia associated with hepatic cirrhosis, TRPV4 expression is increased in lipid rafts from the hypothalamus and that this effect may be angiotensin dependent. In this study, we utilized the immortalized neuroendocrine rat hypothalamic 4B cell line to more directly test the effects of angiotensin II (ANG II) on TRPV4 expression and function. Our results demonstrate the expression of corticotropin-releasing factor (CRF) transcripts, for sex-determining region Y (SRY) (male genotype), arginine vasopressin (AVP), TRPV4, and ANG II type 1a and 1b receptor in 4B cells. After a 1-h incubation in ANG II (100 nM), 4B cells showed increased TRPV4 abundance in the plasma membrane fraction, and this effect was prevented by the ANG II type 1 receptor antagonist losartan (1 μM) and by a Src kinase inhibitor PP2 (10 μM). Ratiometric calcium imaging experiments demonstrated that ANG II incubation potentiated TRPV4 agonist (GSK 1016790A, 20 nM)-induced calcium influx (control 18.4 ± 2.8% n = 5 and ANG II 80.5 ± 2.4% n = 5). This ANG II-induced increase in calcium influx was also blocked by 1 μM losartan and 10 μM PP2 (losartan 26.4 ± 3.8% n = 5 and PP2 19.7 ± 3.9% n = 5). Our data suggests that ANG II can increase TRPV4 channel membrane expression in 4B cells through its action on AT1R involving a Src kinase pathway.

Download Full-text

Role of transient receptor potential vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00406.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. L1173-L1181 ◽

Cited By ~ 59

Author(s):

Zsuzsanna Helyes ◽

Krisztián Elekes ◽

József Németh ◽

Gábor Pozsgai ◽

Katalin Sándor ◽

...

Keyword(s):

Airway Inflammation ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Bronchial Hyperreactivity ◽

Whole Body ◽

Transient Receptor Potential Vanilloid ◽

Wild Type ◽

Trpv1 Receptors ◽

Transient Receptor

Airways are densely innervated by capsaicin-sensitive sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) receptors/ion channels, which play an important regulatory role in inflammatory processes via the release of sensory neuropeptides. The aim of the present study was to investigate the role of TRPV1 receptors in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological, and biochemical techniques using receptor gene-deficient mice. Inflammation was evoked by intranasal administration of Escherichia coli lipopolysaccharide (60 μl, 167 μg/ml) in TRPV1 knockout (TRPV1−/−) mice and their wild-type counterparts (TRPV1+/+) 24 h before measurement. Airway reactivity was assessed by unrestrained whole body plethysmography, and its quantitative indicator, enhanced pause (Penh), was calculated after inhalation of the bronchoconstrictor carbachol. Histological examination and spectrophotometric myeloperoxidase measurement was performed from the lung. Somatostatin concentration was measured in the lung and plasma with radioimmunoassay. Bronchial hyperreactivity, histological lesions (perivascular/peribronchial edema, neutrophil/macrophage infiltration, goblet cell hyperplasia), and myeloperoxidase activity were significantly greater in TRPV−/− mice. Inflammation markedly elevated lung and plasma somatostatin concentrations in TRPV1+/+ but not TRPV1−/− animals. In TRPV1−/− mice, exogenous administration of somatostatin-14 (4 × 100 μg/kg ip) diminished inflammation and hyperreactivity. Furthermore, in wild-type mice, antagonizing somatostatin receptors by cyclo-somatostatin (4 × 250 μg/kg ip) increased these parameters. This study provides the first evidence for a novel counterregulatory mechanism during endotoxin-induced airway inflammation, which is mediated by somatostatin released from sensory nerve terminals in response to activation of TRPV1 receptors of the lung. It reaches the systemic circulation and inhibits inflammation and consequent bronchial hyperreactivity.

Download Full-text