Pregnenolone Sulphate- and Cholesterol-Regulated TRPM3 Channels Coupled to Vascular Smooth Muscle Secretion and Contraction

Naylor, Jacqueline; Li, Jing; Milligan, Carol J.; Zeng, Fanning; Sukumar, Piruthivi; Hou, Bing; Sedo, Alicia; Yuldasheva, Nadira; Majeed, Yasser; Beri, Dhananjay; Jiang, Shan; Seymour, Victoria A. L.; McKeown, Lynn; Kumar, Bhaskar; Harteneck, Christian; O’Regan, David; Wheatcroft, Stephen; Kearney, Mark T.; Jones, Clare A.; Porter, Karen E.; Beech, David J.

doi:10.1161/circresaha.110.219329

Cited by 132 publications

(120 citation statements)

References 33 publications

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“…Based on current, limited, knowledge of TRPM3 functions, it would be anticipated that consequences of blocking TRPM3 would be reduced insulin secretion from the pancreas, increased interleukin secretion from vascular smooth muscle cells, and increased hyaluronan secretion from synovial fibroblasts of patients with rheumatoid arthritis (Wagner et al, 2008;Ciurtin et al, 2010;Naylor et al, 2010). All of these effects would presumably be unwanted, consistent with the emerging concept of TRPM3 as a beneficial ion channel that is stimulated by "fountain of youth" steroids.…”

Section: Discussionmentioning

confidence: 93%

“…The strongest known activator of TRPM3 channels is pregnenolone sulfate (Wagner et al, 2008;Majeed et al, 2010). However, the concentrations of pregnenolone sulfate required for activation are supraphysiological (Wagner et al, 2008;Naylor et al, 2010). Other strong activators of TRPM3 are not known but they may not be required because constitutive cholesterol-regulated activity is possible .…”

Section: Introductionmentioning

confidence: 99%

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Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Majeed¹,

Bahnasi²,

Seymour³

et al. 2011

Mol Pharmacol

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The aim of this study was to generate new insight into chemical regulation of transient receptor potential (TRP) channels with relevance to glucose homeostasis and the metabolic syndrome. Human TRP melastatin 2 (TRPM2), TRPM3, and TRP canonical 5 (TRPC5) were conditionally overexpressed in human embryonic kidney 293 cells and studied by using calciummeasurement and patch-clamp techniques. Rosiglitazone and other peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists were investigated. TRPM2 was unaffected by rosiglitazone at concentrations up to 10 M but was inhibited completely at higher concentrations (IC 50 , ϳ22.5 M). TRPM3 was more potently inhibited, with effects occurring in a biphasic concentration-dependent manner such that there was approximately 20% inhibition at low concentrations (0.1-1 M) and full inhibition at higher concentrations (IC 50 , 5-10 M). PPAR-␥ antagonism by 2-chloro-5-nitrobenzanilide (GW9662) did not prevent inhibition of TRPM3 by rosiglitazone. TRPC5 was strongly stimulated by rosiglitazone at concentrations of Ն10 M (EC 50 , ϳ30 M). Effects on TRPM3 and TRPC5 occurred rapidly and reversibly. Troglitazone and pioglitazone inhibited TRPM3 (IC 50 , 12 M) but lacked effect on TRPC5, suggesting no relevance of PPAR-␥ or the thiazolidinedione moiety to rosiglitazone stimulation of TRPC5. A rosiglitazone-related but, was a weak stimulator of TRPM3 and TRPC5. The natural PPAR-␥ agonist 15-deoxy prostaglandin J 2 , had no effect on TRPM3 or TRPC5. The data suggest that rosiglitazone contains chemical moieties that rapidly, strongly, and differentially modulate TRP channels independently of PPAR-␥, potentially contributing to biological consequences of the agent and providing the basis for novel TRP channel pharmacology.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Majeed¹,

Bahnasi²,

Seymour³

et al. 2011

Mol Pharmacol

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“…TRPM3 channels are expressed in various tissues, including the kidney, liver, ovary, brain, spinal cord, pituitary gland, vascular smooth muscle, testis, and b-cells of the pancreas (Grimm et al, 2003;Lee et al, 2003;Oberwinkler et al, 2005;Wagner et al, 2008;Naylor et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential Melastatin-3 (TRPM3)–Induced Activation of AP-1 Requires Ca²⁺ Ions and the Transcription Factors c-Jun, ATF2, and Ternary Complex Factor

et al. 2015

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The steroid pregnenolone sulfate activates the transcription factor activator protein-1 (AP-1) via stimulation of transient receptor potential melastatin-3 (TRPM3) channels. Here, we show that the signaling pathway requires an influx of Ca 21 ions into the cells and a rise in the intracellular Ca 21 levels. The upregulation of AP-1 was attenuated in cells that overexpressed mitogen activated protein kinase phosphatase-1, indicating that Ca 21 ions prolong the signaling cascade via activation of mitogen activated protein kinases. On the transcriptional level, expression of a dominant-negative mutant of the basic region leucine zipper protein c-Jun, a major constituent of the AP-1 transcription factor complex, or expression of a c-Jun-specific short hairpin RNA attenuated pregnenolone sulfate-induced AP-1 activation. In addition, stimulation of TRPM3 channels increased the transcriptional activation potential of the basic region leucine zipper protein ATF2. Inhibition of ATF2 target gene expression via expression of a dominant-negative mutant of ATF2 or expression of an ATF2-specific short hairpin RNA interfered with TRPM3-mediated stimulation of AP-1. Moreover, we show that a dominant-negative mutant of the ternary complex factor (TCF) Elk-1 attenuated the upregulation of AP-1 following stimulation of TRPM3 channels. Thus, c-Jun, ATF2, and TCFs are required to connect the intracellular signaling cascade elicited by activation of TRPM3 channels with enhanced transcription of AP-1-regulated genes. We conclude that pregnenolone sulfateinduced TRPM3 channel activation changes the gene expression pattern of the cells by activating transcription of c-Jun-, ATF2-, and TCF-controlled genes.

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“…Pregnenolone Sulfate-and Cholesterol-Regulated TRPM3 Channels Coupled to Vascular Smooth Muscle Secretion and Contraction; Naylor et al 117 What Is Known?…”

Section: Resultsmentioning

confidence: 99%

Circulation Research Thematic Synopsis

2012

Circulation Research

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Circulation Research Thematic Synopses:The goal of Thematic Synopses is to provide our readers with a concise but comprehensive overview of the work published in Circulation Research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. These collections of articles are organized thematically and are listed in chronological order, beginning with the most recent ones. In each synopsis, the top downloaded original research articles (normalized to time since publication) are highlighted in yellow. Review articles also are included, with titles highlighted in blue, and the summary of each is provided. Instead of using abstracts, we have elected to publish the Novelty and Significance section of each article, which we believe provides a clear précis of the salient findings and their implications in a language that is easily understandable by the noninitiated. This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields. It is our hope and expectation that Thematic Synopses will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research. -The Editors Circulation Research Thematic Synopsis AtherosclerosisThe Editors D espite an approximately 40% reduction in mortality during the past 30 years, cardiovascular diseases remain the number one cause of death in the United States (http://www.cdc.gov/nchs/fastats/heart.htm) and globally (http://www.who.int/mediacenter/factsheets/fs317/en/index.html) (both accessed on July 15, 2012). The threat is unabated, because cardiovascular diseases, with atherosclerosis and its thrombotic complications leading the way, are projected to remain the single leading cause of death in the world in the next 20 years (http://www.who.int/mediacenter/factsheets/ fs317/en/index.html). Justifiably, it is not surprising that the molecular pathogenesis of atherosclerosis and acute thrombotic syndromes continues to remain the subject of intense research. In conjunction with the intense laboratory research and in view of the enormous burden of cardiovascular diseases, which claim approximately 800 000 lives per year in the United States alone, 1 the United States Department of Health and Human Services along with the American Heart Association and other organizations has launched the "Million Hearts" initiatives aimed at preventing 1 million myocardial infarctions (MIs) and strokes over the next 5 years (http://www.cdc.gov/24 -7/prevention/MillionHearts/ accessed July 15, 2012).Despite the intense research and heightened interest, delineation of the complete spectrum of etiologies in atherosclerosis has remained largely elusive. Perhaps the most direct and robust evidence for the causal factors in atherosclerosis originated from the genetic studies of rare Mendelian diseases, such as familial hypercholesterolemia and Tangier disease. The disc...

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Pregnenolone Sulphate- and Cholesterol-Regulated TRPM3 Channels Coupled to Vascular Smooth Muscle Secretion and Contraction

Cited by 132 publications

References 33 publications

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Transient Receptor Potential Melastatin-3 (TRPM3)–Induced Activation of AP-1 Requires Ca²⁺ Ions and the Transcription Factors c-Jun, ATF2, and Ternary Complex Factor

Circulation Research Thematic Synopsis

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Pregnenolone Sulphate- and Cholesterol-Regulated TRPM3 Channels Coupled to Vascular Smooth Muscle Secretion and Contraction

Cited by 132 publications

References 33 publications

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Rapid and Contrasting Effects of Rosiglitazone on Transient Receptor Potential TRPM3 and TRPC5 Channels

Transient Receptor Potential Melastatin-3 (TRPM3)–Induced Activation of AP-1 Requires Ca2+ Ions and the Transcription Factors c-Jun, ATF2, and Ternary Complex Factor

Circulation Research Thematic Synopsis

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Transient Receptor Potential Melastatin-3 (TRPM3)–Induced Activation of AP-1 Requires Ca²⁺ Ions and the Transcription Factors c-Jun, ATF2, and Ternary Complex Factor