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Pharmaceutical Processing |
Diverse asthma treatment pipeline presents major investment opportunity
Pharmaceutical Processing The active and diverse treatment pipeline for asthma boasts a striking level of innovation, with many first-in-class products representing significant investment opportunities, says business intelligence provider GBI Research. The company's latest … |
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Diverse Asthma Treatment Pipeline Presents Major Investment Opportunity, says …
Drug Discovery & Development The company's latest report* states that while asthma therapy development is dominated by small molecule compounds, with 156 products representing 67% of the pipeline, the research and development landscape has moved towards biologics on an … |
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Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions.
Pharmacol Rev. 2013;65(2):670-709
Authors: Schmidt M, Dekker FJ, Maarsingh H
Abstract
Since the discovery nearly 60 years ago, cAMP is envisioned as one of the most universal and versatile second messengers. The tremendous feature of cAMP to tightly control highly diverse physiologic processes, including calcium homeostasis, metabolism, secretion, muscle contraction, cell fate, and gene transcription, is reflected by the award of five Nobel prizes. The discovery of Epac (exchange protein directly activated by cAMP) has ignited a new surge of cAMP-related research and has depicted novel cAMP properties independent of protein kinase A and cyclic nucleotide-gated channels. The multidomain architecture of Epac determines its activity state and allows cell-type specific protein-protein and protein-lipid interactions that control fine-tuning of pivotal biologic responses through the “old” second messenger cAMP. Compartmentalization of cAMP in space and time, maintained by A-kinase anchoring proteins, phosphodiesterases, and ?-arrestins, contributes to the Epac signalosome of small GTPases, phospholipases, mitogen- and lipid-activated kinases, and transcription factors. These novel cAMP sensors seem to implement certain unexpected signaling properties of cAMP and thereby to permit delicate adaptations of biologic responses. Agonists and antagonists selective for Epac are developed and will support further studies on the biologic net outcome of the activation of Epac. This will increase our current knowledge on the pathophysiology of devastating diseases, such as diabetes, cognitive impairment, renal and heart failure, (pulmonary) hypertension, asthma, and chronic obstructive pulmonary disease. Further insights into the cAMP dynamics executed by the Epac signalosome will help to optimize the pharmacological treatment of these diseases.
PMID: 23447132 [PubMed – as supplied by publisher]
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 Diverse: Issues in Higher Educatio |
Johns Hopkins Launches Study of Genetic Drivers of Asthma in Blacks
Diverse: Issues in Higher Educatio With a disproportionate share of medical research previously enrolling mainly White study participants, this Black-focused asthma research represents an essential departure. “The genetic and genomic roots are significant,” said Dr. Fernando Martinez, … |
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The G protein-coupled receptor OGR1 mediates diverse signaling and contraction of airway smooth muscle in response to small reductions in extracellular pH.
Br J Pharmacol. 2011 Dec 6;
Authors: Saxena H, Deshpande DA, Tiegs BC, Yan H, Battafarano RJ, Burrows WM, Damera G, Panettieri RA, Dubose TD, An SS, Penn RB
Abstract
Background and Purpose.? Previous studies have linked a reduction of pH in the airway, caused by either environmental factors, microaspiration of gastric acid, or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown capable of mediating airway contraction in response to reductions in airway pH to values of < pH 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. Experimental Approach.? Intracellular signaling events stimulated by ?pHo in cultured human ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using Magnetic Twisting Cytometry. Expression of putative proton-sensing G protein-coupled receptors (GPCRs) in ASM was assessed by real-time PCR. The role of OGR1 in acid-induced ASM signaling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. Key Results.? ASM cells responded to incremental reductions in pHo (from pH 8.0-6.8) by activating multiple signaling pathways, involving p42/p44, Akt, PKA, and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar “dose” dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signaling (excepting Akt activation) and contraction were significantly attenuated by knockdown of OGR1. Conclusions and Implications.? These studies reveal OGR1 to be a physiologically-relevant GPCR in ASM cells, capable of pleiotropic signaling and mediation of contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.
PMID: 22145625 [PubMed – as supplied by publisher]
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 UCSF News Services |
New Asthma Risk Gene Emerges from Study of Diverse Populations
UCSF News Services Asthma rates in the United States are higher among African Americans and Latinos in comparison to European Americans, but the causes of asthma in all populations still are only poorly understood. … |
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