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Posts Tagged ‘G protein-coupled receptor’


Lesson 3 Cell Signaling & Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Lesson 3 Powerpoint (click link below):

cell signaling and motility 3 finalissima sjw

Four papers to choose from for your February 11 group presentation:

Structural studies of G protein Coupled receptor

Shapiro-2009-Annals_of_the_New_York_Academy_of_Sciences

G protein as target in neurodegerative disease

fish technique

 

 

Today’s lesson 3 explains how extracellular signals are transduced (transmitted) into the cell through receptors to produce an agonist-driven event (effect).  This lesson focused on signal transduction from agonist through G proteins (GTPases), and eventually to the effectors of the signal transduction process.  Agonists such as small molecules like neurotransmitters, hormones, nitric oxide were discussed however later lectures will discuss more in detail the large growth factor signalings which occur through receptor tyrosine kinases and the Ras family of G proteins as well as mechanosignaling through Rho and Rac family of G proteins.

Transducers: The Heterotrimeric G Proteins (GTPases)

An excellent review of heterotrimeric G Proteins found in the brain is given by

Heterotrimeric G Proteins by Eric J Nestler and Ronald S Duman.

 

 

from Seven-Transmembrane receptors – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Examples-of-heterotrimeric-G-protein-effectors_tbl1_11180073 [accessed 4 Feb, 2019] and see references within

 

 

See below for the G Protein Cycle

 

 

 

 

 

 

 

 

<a href=”https://www.researchgate.net/figure/32-The-G-protein-cycle-In-the-absence-of-agonist-A-GPCRs-are-mainly-in-the-low_fig2_47933733″><img src=”https://www.researchgate.net/profile/Veli_Pekka_Jaakola/publication/47933733/figure/fig2/AS:669499451781133@1536632516635/32-The-G-protein-cycle-In-the-absence-of-agonist-A-GPCRs-are-mainly-in-the-low.ppm&#8221; alt=”.3.2: The G protein cycle. In the absence of agonist (A), GPCRs are mainly in the low affinity state (R). After agonist binding, the receptor is activated in the high affinity state (R*), and the agonist-GPCR-G protein complex is formed. GTP replaces GDP in Gα. After that the G protein dissociates into the Gα subunit and the Gβγ heterodimer, which then activate several effector proteins. The built-in GTPase activity of the Gα subunit cleaves the terminal phosphate group of GTP, and the GDP bound Gα subunit reassociates with Gβγ heterodimer. This results in the deactivation of both Gα and Gβγ. The G protein cycle returns to the basal state. RGS, regulator of G protein signalling.”/></a>

 

From Citation: Review: A. M. Preininger, H. E. Hamm, G protein signaling: Insights from new structures. Sci. STKE2004, re3 (2004)

 

For a tutorial on G Protein coupled receptors (GPCR) see

https://www.khanacademy.org/test-prep/mcat/organ-systems/biosignaling/v/g-protein-coupled-receptors

 

 

 

cyclic AMP (cAMP) signaling to the effector Protein Kinase A (PKA)

from https://courses.washington.edu/conj/gprotein/cyclicamp.htm

Cyclic AMP is an important second messenger. It forms, as shown, when the membrane enzyme adenylyl cyclase is activated (as indicated, by the alpha subunit of a G protein).

 

The cyclic AMP then goes on the activate specific proteins. Some ion channels, for example, are gated by cyclic AMP. But an especially important protein activated by cyclic AMP is protein kinase A, which goes on the phosphorylate certain cellular proteins. The scheme below shows how cyclic AMP activates protein kinase A.

Additional information on Nitric Oxide as a Cellular Signal

Nitric oxide is actually a free radical and can react with other free radicals, resulting in a very short half life (only a few seconds) and so in the body is produced locally to its site of action (i.e. in endothelial cells surrounding the vascular smooth muscle, in nerve cells). In the late 1970s, Dr. Robert Furchgott observed that acetylcholine released a substance that produced vascular relaxation, but only when the endothelium was intact. This observation opened this field of research and eventually led to his receiving a Nobel prize. Initially, Furchgott called this substance endothelium-derived relaxing factor (EDRF), but by the mid-1980s he and others identified this substance as being NO.

Nitric oxide is produced from metabolism of endogenous substances like L-arginine, catalyzed by one of three isoforms of nitric oxide synthase (for link to a good article see here) or release from exogenous compounds like drugs used to treat angina pectoris like amyl nitrate or drugs used for hypertension such as sodium nitroprusside.

The following articles are a great reference to the chemistry, and physiological and pathological Roles of Nitric Oxide:

46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

Biochemistry of the Coagulation Cascade and Platelet Aggregation: Nitric Oxide: Platelets, Circulatory Disorders, and Coagulation Effects

Nitric Oxide Function in Coagulation – Part II

Nitric oxide is implicated in many pathologic processes as well.  Nitric oxide post translational modifications have been attributed to nitric oxide’s role in pathology however, although the general mechanism by which nitric oxide exerts its physiological effects is by stimulation of soluble guanylate cyclase to produce cGMP, these post translational modifications can act as a cellular signal as well.  For more information of NO pathologic effects and how NO induced post translational modifications can act as a cellular signal see the following:

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.

https://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

Note:  A more comprehensive ebook on Nitric Oxide and Disease Perspectives is found at

Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

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Intravenous drug for the treatment of Acute Heart Failure (AHF) by Trevena, Inc. (Trevena) – Leader in the Discovery of G-protein coupled receptor (GPCR) biased ligands

Reporter: Aviva Lev-Ari, PhD, RN

Cardiovascular biotech Trevena files for a $86 million IPO

10/9/13

Trevena, a clinical-stage biotech developing a treatment for acute heart failure, filed on Wednesday with the SEC to raise up to $86 million in an initial public offering. The King of Prussia, PA-based company, which was founded in 2007 and booked $1 million in grant and collaboration revenue for the 12 months ended June 30, 2013, plans to list on the NASDAQ under the symbol TRVN. Trevena initially filed confidentially on September 6, 2013. Barclays and Jefferies are the joint bookrunners on the deal. No pricing terms were disclosed.

Keywords/Tickers: TRVN

Trevena (TRVN) Files $86.25M IPO

October 9, 2013 3:42 PM EDT   

Trevena, Inc. (Nasdaq: TRVN) filed a registration with the U.S. Securities and Exchange Commission for an Initial Public Offering of its Common Stock. The proposed maximum offering price is $86.25 million. The company plans to list on the NasdaqGlobal Market under the ticker, TRVN.The offering is being made via BarclaysJefferies, Canaccord Genuity, JMP Securities, and Needham & Company

Trevena a clinical stage biopharmaceutical company that discovers, develops and intends to commercialize therapeutics that use a novel approach to target G protein coupled receptors, or GPCRs.

Heart Biotech Trevena, Inc. Files for a $86 Million IPO

10/10/2013 9:19:18 AM

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Trevena, Inc. (Nasdaq: TRVN) filed a registration with the U.S. Securities and Exchange Commission for an Initial Public Offering of its Common Stock. The proposed maximum offering price is $86.25 million. The company plans to list on the Nasdaq Global Market under the ticker, “TRVN.” The offering is being made via Barclays, Jefferies, Canaccord Genuity, JMP Securities, and Needham & Company.

http://www.biospace.com/news_story.aspx?NewsEntityId=311439&type=email&source=GP_101013

Journal of Clinical Pharmacology Publishes First Clinical Experience With Trevena, Inc.‘s Heart Failure Biased Ligand TRV027

7/8/2013 2:56:28 PM

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KING OF PRUSSIA, Pa., July 8, 2013 /PRNewswire/ — Trevena, Inc. (Trevena), a clinical stage pharmaceutical company and the leader in the discovery of G-protein coupled receptor (GPCR) biased ligands, today announced the electronic publication of Trevena’s manuscript, “First Clinical Experience with TRV027: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers.” The manuscript can be viewed online at the Journal of Clinical Pharmacology’s website (http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4604/ earlyview).

TRV027 is an experimental intravenous drug now in mid-stage clinical trials for the treatment of acute heart failure (AHF). The printed manuscript will appear in a future print issue of the journal. David G. Soergel, M.D., Trevena’s Senior Vice President of Clinical Development, Jonathan D. Violin, PhD, Director of Biology and Co-Founder of Trevena, and Michael W. Lark, PhD, Trevena’s Chief Scientific Officer and Senior Vice President of Research at Trevena, were among the publication’s authors.

The manuscript summarizes results from the first-in-human clinical study in which the compound was administered to healthy human subjects. In this study, the tolerability, pharmacokinetics and pharmacodynamics of multiple doses of TRV027 were explored. TRV027 was safe and well-tolerated, with a usefully short half-life and dose-proportional increases in systemic exposure. The compound showed a decrease in mean arterial pressure in subjects that had an elevation in their renin angiotensin aldosterone system, a common characteristic in AHF patients. TRV027’s activity, observed in the study, is consistent with its mechanism of action and previously published preclinical findings.

“In this phase 1 study, we successfully translated the unique activity profile of TRV027 from preclinical species into humans. These data supported our decision to progress TRV027 into Phase 2 studies in heart failure patients,” commented Dr. Soergel.

About TRV027 and AHF

TRV027 is a novel beta-arrestin biased ligand of the angiotensin II type 1 receptor (AT1R) that combines the proven benefits of angiotensin blockade with new beta-arrestin-mediated biology to preserve cardiac and renal function. TRV027 is being developed by Trevena under a recently announced collaborative licensing option agreement with Forest Laboratories Inc. For more details, please find a copy of the May 9, 2013 press release on the Trevena website, under the “News” tab (http://www.trevenainc.com/).

In March 2013, Trevena also presented the results of a Phase 2a study on the hemodynamic effects of TRV027 in patients with advanced systolic heart failure as a poster at the annual American College of Cardiology meeting. Completion of the ascending dose-titration Phase 2a study was announced in October 2012, in which the safety, tolerability, pharmacokinetics, and invasive hemodynamics of TRV027 (formally TRV120027) was measured (NCT01187836). The drug was generally well-tolerated and produced a beneficial set of hemodynamic effects in the study. A phase 2b clinical trial of TRV027 is expected to begin later this year.

The American Heart Association estimated that AHF hospitalization costs the U.S. healthcare system more than $20 billion each year in direct spending. AHF is already the leading reason for hospitalization of individuals over 65 years old in the United States, with over 1 million hospital admissions per year. AHF is also the most costly diagnosis for Medicare in the nation. Despite the significance of this problem, current therapies are not producing meaningful improvements in patient outcomes. AHF incidence is increasing globally, and both heart failure mortality and hospital re-admission following an AHF event remain extremely high.

About Trevena

Trevena, Inc. is dedicated to discovering and developing the next generation of GPCR targeted medicines. GPCRs are the targets for at least one-third of modern medicinal products, and remain the predominant class of targets under clinical evaluation. Trevena’s expertise lies in engineering “biased ligands” that activate only the beneficial signaling pathways downstream of a GPCR to unlock new biology and avoid drug adverse effects. In addition to TRV027, Trevena’s pipeline currently includes a clinical stage mu-opioid biased ligand for post-operative pain, and discovery-stage programs for chronic pain and Parkinson’s disease.

http://www.biospace.com/News/journal-of-clinical-pharmacology-publishes-first/302084

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