A2B adenosine receptor in rat skeletal muscle cells: Signaling and functionality
- مجال مشروع البحث–الرئيسي
- العلوم الطبية والصحية
- مجال مشروع البحث–الثانوي
- العلوم الصيدلانية
- المؤسسة العلمية
- جامعة فيلادلفيا
- المحافظة
- عمان
- قيمة الدعم
- JD13994.84
- سنة الدعم
- 2015
- حالة المشروع
- منتهي مع النشر
- البحث منشور
- (1) Haddad, M. (2016). The impact of adenosine A2B receptors modulation on nuclear receptors (NR4A) gene expression. Biomedical and Pharmacology Journal, 9(1), 177-185.
(2) Haddad, M. (2017). Adenosine A2B Receptors-Mediated Induction of Interleukin-6 in Skeletal Muscle Cells. Turkish Journal of Pharmaceutical Sciences, 14(1), 19.
(3) Haddad, M. (2016). THE IMPACT OF ADENOSINE A2B RECEPTORS MODULATION ON PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA CO-ACTIVATOR 1-ALPHA AND TRANSCRIPTION FACTORS. International Journal of Pharmaceutical Sciences and Research, 7(12), 4762.
(4) Haddad, M. (2016). THE EFFECT OF NECA, CGS 21680, PSB 603 ON FATTY ACID TRANSPORT AND OXIDATION IN SKELETAL MUSCLE CELLS. International Journal of Pharmaceutical Sciences and Research, 7(12), 4827.
(5) Haddad, M. (2016). THE IMPACT OF ADENOSINE A2B RECEPTORS ON GLYCOLYSIS AND INSULIN RESISTANCE IN SKELETAL MUSCLE. International Journal of Pharmaceutical Sciences and Research, 7(12), 4917.
- ملخص عن مشروع البحث
- 1. Adenosine is a ubiquitous signalling molecule, of which the majority of the effects are mediated by interaction with its four G-protein-coupled receptors (A1, A2A, A2B and A3) 1. It has been proposed that adenosine modulates different functional activities in skeletal muscle cells. Previous studies have demonstrated that the activation of adenosine A2B receptors increases adenosine 3'-cyclic monophosphate (cAMP) accumulation in rat skeletal muscle cells 2, which is probably an important yet unknown mechanism contributing to the regulation of skeletal muscle functions. Using rat L6 skeletal muscle cells, I elucidate further potential molecular signalling responsible for adenosine A2B receptor modulations. Skeletal muscle cells are commonly employed cells, and have been previously described as expressing adenosine receptors 3. Quantitative real-time PCR assays (probe-based) are used to evaluate the gene expression profiles of adenosine A2B receptor signalling. In this study, I show that adenosine A2B receptors are functionally expressed in skeletal muscle cells, as indicated by the fact that the activation of adenosine A2B receptors increases the NR4A mRNA gene expression level using qRT-PCR. Previous studies have shown that the nonselective adenosine A2B receptor agonist NECA, but not the adenosine A2A receptor selective agonist CGS 21680, induces cAMP accumulations 2. The effect of NECA is blocked by the selective antagonist of adenosine A2B receptors, PSB 6032. In the current study, NECA (10μM) increases NR4A1, NR4A2 and NR4A3 mRNA gene expression significantly (a 5.9-, 2.9- and 2.4-fold change to vehicle, respectively), which are blocked by a selective adenosine A2B receptor antagonist, PSB 603 (100 nM). This current study identifies the adenosine A2B receptors as a significant regulator of NR4A mRNA gene expression in skeletal muscle, thereby pointing to its therapeutic potential. In summary, I observe the selective, potentially functional expression of adenosine A2B receptors in skeletal muscle cells. Whether adenosine A2B receptor-mediated functional responses play a role in skeletal muscle pathophysiology is yet to be elucidated.
https://biomedpharmajournal.org/vol9no1/the-impact-of-adenosine-a2b-receptors-modulation-on-nuclear-receptors-nr4a-gene-expression/
2. Objectives:Inflammatory response and cytokine activation are markedly stimulated in skeletal muscle during various conditions. Interleukin-6 (IL-6), a pro-inflammatory cytokine, has pleiotropic effects on skeletal muscle. Adenosine, released by all cell types, binds to a class of G protein-coupled receptors to induce various skeletal muscle effects. The aim of this work was to investigate whether activation of adenosine receptors, particularly adenosine A2B receptors, could stimulate IL-6 gene expression in rat L6 skeletal muscle cells.
Materials and Methods:The rat L6 skeletal muscle cells were cultured in 25 cm2 flasks. These differentiated cells were treated and then quantitative reverse transcription-polymerase chain reaction (Probe-based) was used to analyze IL-6 gene expression level among different treatment conditions. Results:Adenosine-5′-N-ethyluronamide (NECA), a stable adenosine analogue, concentration- and time-dependently stimulates IL-6 gene expression in skeletal muscle cells. The effect of NECA is inhibited by a selective adenosine A2B receptor antagonist, PSB 603. By using cyclic adenosine monophosphate (cAMP)-arising reagent forskolin, cAMP is found to be involved in the up-regulation of IL-6 induction.
Conclusion:Here, a novel relationship between adenosine and IL-6 up-regulation has been demonstrated for the first time; IL-6 up-regulation induced by NECA is mediated by adenosine A2B receptor activation in skeletal muscle and is dependent on mainly a cAMP pathway. Adenosine A2B receptors are, thus, potentially important pharmacological targets in treating inflammation and related diseases in skeletal muscle tissues.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227993/
3. Previous studies have demonstrated that the activation of adenosine A2B receptors increases adenosine 3'-cyclic monophosphate (cAMP) accumulation in rat
skeletal muscle cells, which is probably an important yet unknown mechanism contributing to the regulation of skeletal muscle functions. via rat L6 skeletal muscle
cells, it has been elucidated further potential molecular signaling responsible for adenosine A2B receptor modulations via quantitative real-time PCR assays (probe_x0002_based). The results of the present study has shown for the first time that NECA alters the expression of PGC-1α significantly in both one week and 19 hours starved skeletal
muscle cells (P<0.05 and P<0.01, respectively) (2.5 and -0.58 fold change compared to vehicle, respectively). Adenosine A2B receptors mediate NECA-modulated PGC-1α
mRNA gene expression in skeletal muscle cells. To our knowledge, this is the first study demonstrating an induction of PGC-1α gene by CGS 21680 significantly (P<0.001)
(around 1.8 fold change compared to vehicle). In the current study, NECA (10 μM) increases NR4A1 and NR4A3 mRNA gene expression significantly (P<0.05) (around
2.7 and 5.2 -fold change to vehicle, respectively), which are blocked by a selective adenosine A2B receptor antagonist, PSB 603. This current study identifies the adenosine
A2B receptors as a significant regulator of PGC-1α, NR4A1 and NR4A3 mRNA gene expression in skeletal muscle, thereby pointing to its therapeutic potential. In summary, it
has been observed the selective, potentially functional expression of adenosine A2 receptors in skeletal muscle cells. Whether adenosine A2 receptor mediated functional
responses play a role in skeletal muscle pathophysiology is yet to be elucidated.
https://www.researchgate.net/profile/Mansour-Haddad-3/publication/317828160_THE_IMPACT_OF_ADENOSINE_A2B_RECEPTORS_MODULATION_ON_PEROXISOME_PROLIFERATOR-ACTIVATED_RECEPTOR_GAMMA_CO-ACTIVATOR_1-ALPHA_AND_TRANSCRIPTION_FACTORS/links/594d165d0f7e9b49c70f8a82/THE-IMPACT-OF-ADENOSINE-A2B-RECEPTORS-MODULATION-ON-PEROXISOME-PROLIFERATOR-ACTIVATED-RECEPTOR-GAMMA-CO-ACTIVATOR-1-ALPHA-AND-TRANSCRIPTION-FACTORS.pdf
4. Adenosine is a strong modulator of gene expression, which underpins some of its potential expected effects in skeletal muscle in terms of fatty acid metabolism. Accumulating evidence highlights a critical role for the adenosine system in the regulation of fatty acid metabolism and obesity. However, its molecular signaling role in fatty acid transport and oxidation in skeletal muscle is less clear. The aim of the present study was to examine whether acute and chronic treatment of skeletal muscle cells in vitro with stable adenosine analogue NECA, selective adenosine A2B receptors antagonist/inverse agonist PSB 603, and/or selective adenosine A2A receptors agonist CGS 21680 affects mRNA expression of key metabolic genes in skeletal muscle. Rat L6 skeletal muscle cells were treated with NECA, PSB 603 and CGS 21680 for determination the mRNA expression of genes involved in fatty acid transport and oxidation (CPT1B, ACCβ and LCAD) using QRT-PCR (Probe-based). The results of the present study have shown for the first time that NECA alters the expression of a number of genes (CPT1B, ACCβ and LCAD). Moreover, this is the first study demonstrating that PSB 603 alters the expression of a number of genes (CPT1B, and ACCβ). To our knowledge, this is the first study demonstrating an alteration of CPT1B, and LCAD genes by CGS 21680. Adenosine A2B receptors mediate both NECA-induced LCAD, NECA-inhibited ACCβ, and NECA-modulated CPT1B mRNA gene expression in skeletal muscle cells. Collectively, these data reveal adenosine A2B receptors as a novel target to
consider in our understanding of metabolic function in skeletal muscle and risk for the development of metabolic-based diseases.
https://www.researchgate.net/profile/Mansour-Haddad-3/publication/317828289_THE_EFFECT_OF_NECA_CGS_21680_PSB_603_ON_FATTY_ACID_TRANSPORT_AND_OXIDATION_IN_SKELETAL_MUSCLE_CELLS/links/594d1a0345851543382a6d09/THE-EFFECT-OF-NECA-CGS-21680-PSB-603-ON-FATTY-ACID-TRANSPORT-AND-OXIDATION-IN-SKELETAL-MUSCLE-CELLS.pdf
5. Adenosine has been proposed as a key factor regulating the metabolic balance between energy supply and demand in skeletal muscle. Adenosine A2B
receptors are expressed across multiple tissues including skeletal muscle. Previously, it has been identified the robust (in vitro) induction of the nuclear receptors (NR4A)
subgroup following adenosine A2B receptors stimulation in rat skeletal muscle cells. This may be concomitant with changes in the expression of genes involved in the
regulation of nutrient metabolism. Considering that skeletal muscle is a primary tissue responsible for glucose disposal, glucose oxidation and insulin resistance, this
study investigated a potential functional role for adenosine A2B receptors in rat L6 skeletal muscle myotubes in terms of glycolysis (HKII and PFK), and insulin
resistance/glucose oxidation (PDK4) using a transcriptional approach (QRT-PCR (Probe-based)). For the first time in rat skeletal muscle cells, the results of the
present study have shown that stable adenosine analogue NECA alters the expression of a number of genes (HKII, and PFK). Moreover, this is the first study
demonstrating that selective adenosine A2B receptors antagonist/inverse agonist PSB 603 alters the expression of a number of genes (HKII, PFK, and PDK4). To our
knowledge, this is the first study also demonstrating an alteration of PFK gene by selective adenosine A2A receptors agonist CGS 21680. Adenosine A2B receptors
mediate both NECA (adenosine-5'N-ethylcarboxamide)-induced HKII, and NECAinhibited PFK mRNA gene expression in skeletal muscle cells. These results indicate
that adenosine A2B receptors play a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal adenosine A2B receptors
as a novel target to consider in our understanding of metabolic function and risk for the development of metabolic-based diseases.
hhttps://www.researchgate.net/profile/Mansour-Haddad-3/publication/317828359_THE_IMPACT_OF_ADENOSINE_A2B_RECEPTORS_ON_GLYCOLYSIS_AND_INSULIN_RESISTANCE_IN_SKELETAL_MUSCLE/links/594d19df45851543382a6d05/THE-IMPACT-OF-ADENOSINE-A2B-RECEPTORS-ON-GLYCOLYSIS-AND-INSULIN-RESISTANCE-IN-SKELETAL-MUSCLE.pdf
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