EPINEPHRINE SIGNALING PATHWAY VIA ADRENERGIC RECEPTOR BETA (PW:0000794)
Description
Norepinephrine and epinephrine, whose synthesis and release are prompted by various but distinct stresses, act as neurotransmitters and hormones that signal via various adrenergic receptors, G-protein coupled receptors (GPCR) that couple to distinct G alpha subunits of heterotrimeric G proteins. The beta receptors, for which epinephrine appears to be a favorite agonist, couple to the Gs alpha subunit leading to activation of adenylyl cyclases, cAMP production and subsequent triggering of PKA signaling pathway. Of the three beta receptors, beta1 and beta2 are the better understood systems.The highest levels of beta1 are found in the heart and brain; beta2 is expressed in the heart, lung and other tissues. Beta2, due to its role in smooth muscle relaxation, has been the target for the development of short- and long-acting agonists used in the treatment of asthma. Both receptors are important for the stimulation of cardiac performance. Acute activation of the receptors following ventricular dysfunction, while initially beneficial, can lead to heart failure if it becomes chronic. Upon agonist binding, conformational changes lead to binding of the receptor to the GDP-bound G protein complex. Activated receptors act as GEFs to catalyze the release of GDP from the G alpha subunit followed by formation of a stable receptor-G protein complex. GTP binding to the alpha subunit triggers conformational re-arrangements leading to the dissociation of the GTP-bound G alpha from both the beta/gamma and receptor complexes and association with downstream effectors. For Gs alpha, the effectors are members of the adenylyl cyclase family that catalyze the conversion of ATP to cAMP. G alpha has intrinsic but slow GTPase activity; members of the RGS family act as GAPs to promote GTP hydrolysis, termination of the G-protein signal, and re-formation of the GDP-bound and inactive heterotrimer now ready for another possible cycle of activation. PKA signaling exerts a plethora of effects; among its targets in cardiac myocytes are proteins involved in excitation-contraction coupling. PKA phosphorylates the activated, ligand-bound beta1 and 2 receptors, also targets for phosphorylation by members of the GRK family. Subsequent interaction with beta-arrestin sterically precludes the coupling between the receptor and the G protein, an event referred to as receptor desensitization. Receptor desensitization is a hallmark of heart failure but its exact role in the condition is still to be determined. Beta-blockers, which compete with catecholamine binding to counteract excessive signaling and by the same token allow the system to 're-sensitize', are the main therapeutics used for treatment. Beta-arrestin is also involved in receptor internalization to clathrin-coated pits followed by clathrin-mediated endocytosis and receptor degradation (downregulation) or recycling, as needed. In addition, beta-arrestins also act as scaffolds to trigger G protein independent signaling pathways downstream of beta adrenergic and other GPCR receptors, primarily MAPK cascades. Of note is that in addition to common targets, the two receptors interact with distinct sets of proteins (not shown).
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Pathway Diagram:
Genes in Pathway:
G
Adrb1
adrenoceptor beta 1
ISO
RGD
PMID:19110970
RGD:4140391
NCBI chr 1:255,771,962...255,774,973
Ensembl chr 1:255,771,597...255,807,259
G
Adrb2
adrenoceptor beta 2
ISO
RGD
PMID:19110970
RGD:4140391
NCBI chr18:55,642,459...55,644,501
Ensembl chr18:55,502,903...55,644,512
G
Arrb1
arrestin, beta 1
ISO
RGD
PMID:19229505 PMID:18268361
RGD:5135529 , RGD:4140419
NCBI chr 1:153,837,964...153,912,111
Ensembl chr 1:153,838,078...153,904,061
G
Arrb2
arrestin, beta 2
ISO
RGD
PMID:19229505 PMID:18268361
RGD:5135529 , RGD:4140419
NCBI chr10:55,146,887...55,154,854
Ensembl chr10:55,146,818...55,154,850
G
Gnas
GNAS complex locus
ISO
RGD
PMID:19110970
RGD:4140391
NCBI chr 3:163,071,003...163,136,350
Ensembl chr 3:163,071,417...163,127,262 Ensembl chr 3:163,071,417...163,127,262
G
Grk2
G protein-coupled receptor kinase 2
ISO
RGD
PMID:19110970 PMID:19229505
RGD:4140391 , RGD:5135529
NCBI chr 1:201,580,823...201,601,580
Ensembl chr 1:201,581,480...201,601,582
G
Grk5
G protein-coupled receptor kinase 5
ISO
RGD
PMID:19110970 PMID:19229505
RGD:4140391 , RGD:5135529
NCBI chr 1:260,028,269...260,223,699
Ensembl chr 1:260,028,242...260,218,701
G
Snx13
sorting nexin 13
ISO
RGD
PMID:17173929
RGD:4140388
NCBI chr 6:51,758,258...51,862,260
Ensembl chr 6:51,753,036...51,860,224
Pathway Gene Annotations
Disease Annotations Associated with Genes in the epinephrine signaling pathway via adrenergic receptor beta
Adrb1 Anaphylaxis , Angina Pectoris , aortic valve stenosis , Birth Weight , cardiovascular system disease , chronic obstructive pulmonary disease , congestive heart failure , cystic fibrosis , diabetes mellitus , dilated cardiomyopathy , endomyocardial fibrosis , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Familial Natural Short Sleep 2 , genetic disease , Hyperalgesia , Hyperemia , hyperglycemia , hypertension , Left Ventricular Hypertrophy , low tension glaucoma , myocardial infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , nephrosclerosis , obesity , obstructive sleep apnea , periodontitis , renovascular hypertension , Reperfusion Injury , Stomach Neoplasms , type 1 diabetes mellitus , Ventricular Dysfunction Adrb2 acute kidney failure , AIDS Dementia Complex , Angina Pectoris , asthma , autism spectrum disorder , autistic disorder , Breast Neoplasms , bronchiolitis , cardiomyopathy , cardiovascular system disease , cholangiocarcinoma , chronic obstructive pulmonary disease , congestive heart failure , Coronary Disease , cystic fibrosis , dermatitis , dilated cardiomyopathy , disease of metabolism , end stage renal disease , Experimental Liver Cirrhosis , familial adenomatous polyposis 1 , familial hyperlipidemia , Fibrosis , genetic disease , Graves' disease , Hereditary Neoplastic Syndromes , human immunodeficiency virus infectious disease , Hyperlipoproteinemia Type II , hypertension , Hypertriglyceridemia , hypokalemia , hypothyroidism , Insulin Resistance , interstitial cystitis , kidney disease , Left Ventricular Hypertrophy , Liver Injury , lung disease , Metabolic Syndrome , myasthenia gravis , myocardial infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , myocarditis , Nasal Polyps , nervous system disease , Neurodevelopmental Disorders , obesity , open-angle glaucoma , Paroxysmal Dyspnea , pneumonia , polycystic ovary syndrome , primary open angle glaucoma , Prostatic Neoplasms , psoriasis , pulmonary edema , Reperfusion Injury , sciatic neuropathy , Sepsis , steatotic liver disease , Stomach Neoplasms , toxic shock syndrome , Tremor , type 2 diabetes mellitus , ulcerative colitis , urticaria , Ventricular Dysfunction, Left , Vestibulocochlear Nerve Injuries , viral encephalitis Arrb1 3-methylglutaconic aciduria type 7b , Arteriovenous Fistula , colitis , congestive heart failure , Experimental Arthritis , genetic disease , intellectual disability , liver cirrhosis , major depressive disorder , Transplant Rejection Arrb2 alcohol dependence , Alcoholic Fatty Liver , amphetamine abuse , Arteriovenous Fistula , brain infarction , drug psychosis , Experimental Arthritis , Experimental Liver Cirrhosis , Experimental Liver Neoplasms , genetic disease , glioblastoma , hepatocellular carcinoma , heroin dependence , hypertension , liver cirrhosis , Myocardial Reperfusion Injury , nicotine dependence , opiate dependence , pain agnosia , portal hypertension , renal fibrosis , Tobacco Use Disorder , Transplant Rejection , type 2 diabetes mellitus Gnas acromegaly , ACTH-independent macronodular adrenal hyperplasia , ACTH-independent macronodular adrenal hyperplasia 1 , adrenal gland hyperfunction , Adrenal Gland Neoplasms , adrenocortical carcinoma , Albright's hereditary osteodystrophy , Alzheimer's disease , B-Cell Chronic Lymphocytic Leukemia , brachydactyly , Breast Neoplasms , Cafe-au-Lait Spots , cholangiocarcinoma , Colorectal Neoplasms , Cushing Syndrome , disease of cellular proliferation , Duane retraction syndrome , endocrine system disease , Gallstones , gastric adenocarcinoma , genetic disease , growth hormone secreting pituitary adenoma , head and neck squamous cell carcinoma , hemorrhagic disease , hepatocellular carcinoma , hereditary spastic paraplegia 4 , Heterotopic Ossification , hypertension , Hypoxia , Insulin Resistance , intellectual disability , lung adenocarcinoma , McCune Albright syndrome , melanoma , Metabolic Bone Diseases , neuroblastoma , obesity , Orthostatic Hypotension , pancreatic adenocarcinoma , pancreatic cancer , Parasitic Liver Diseases , pituitary adenoma 3 , Pituitary Neoplasms , polycystic kidney disease , polycystic ovary syndrome , Precocious Puberty , primary hyperaldosteronism , Primary Pigmented Nodular Adrenocortical Disease, 1 , progressive osseous heteroplasia , pseudohypoaldosteronism , pseudohypoparathyroidism , pseudohypoparathyroidism type IB , Pseudohypoparathyroidism Type IC , pseudopseudohypoparathyroidism , Respiration Disorders , sex cord-gonadal stromal tumor , skin melanoma , Tachycardia , Uterine Cervical Neoplasms , withdrawal disorder Grk2 Aicardi-Goutieres Syndrome 3 , allergic contact dermatitis , asphyxiating thoracic dystrophy , bacterial pneumonia , Burns , Cardiomegaly , cardiomyopathy , cardiovascular system disease , Cocaine-Related Disorders , Congenital Abnormalities , congestive heart failure , Diabetic Nephropathies , Embryo Loss , Experimental Arthritis , Experimental Autoimmune Myocarditis , Experimental Liver Cirrhosis , genetic disease , Hyperalgesia , hyperglycemia , hypertension , impotence , Insulin Resistance , intellectual disability , Left Ventricular Hypertrophy , limb ischemia , liver cirrhosis , Myocardial Reperfusion Injury , Neuralgia , opiate dependence , Parkinson's disease , pituitary adenoma , portal hypertension , Pruritus , Recurrent Infections, with Encephalopathy, Hepatic Dysfunction, and Cardiovascular Malformations , rheumatoid arthritis , Right Ventricular Hypertrophy , Sepsis , toxic shock syndrome , Vascular System Injuries Grk5 Alzheimer's disease , cardiovascular system disease , Cocaine-Related Disorders , congestive heart failure , genetic disease , hypertension , Inflammation , liver disease , obstructive lung disease , Parkinson's disease , rheumatoid arthritis , Sepsis , Temporomandibular Joint Disorders Snx13 genetic disease , pleomorphic xanthoastrocytoma
3-methylglutaconic aciduria type 7b Arrb1 acromegaly Gnas ACTH-independent macronodular adrenal hyperplasia Gnas ACTH-independent macronodular adrenal hyperplasia 1 Gnas acute kidney failure Adrb2 adrenal gland hyperfunction Gnas Adrenal Gland Neoplasms Gnas adrenocortical carcinoma Gnas Aicardi-Goutieres Syndrome 3 Grk2 AIDS Dementia Complex Adrb2 Albright's hereditary osteodystrophy Gnas alcohol dependence Arrb2 Alcoholic Fatty Liver Arrb2 allergic contact dermatitis Grk2 Alzheimer's disease Gnas , Grk5 amphetamine abuse Arrb2 Anaphylaxis Adrb1 Angina Pectoris Adrb1 , Adrb2 aortic valve stenosis Adrb1 Arteriovenous Fistula Arrb1 , Arrb2 asphyxiating thoracic dystrophy Grk2 asthma Adrb2 autism spectrum disorder Adrb2 autistic disorder Adrb2 B-Cell Chronic Lymphocytic Leukemia Gnas bacterial pneumonia Grk2 Birth Weight Adrb1 brachydactyly Gnas brain infarction Arrb2 Breast Neoplasms Adrb2 , Gnas bronchiolitis Adrb2 Burns Grk2 Cafe-au-Lait Spots Gnas Cardiomegaly Grk2 cardiomyopathy Adrb2 , Grk2 cardiovascular system disease Adrb1 , Adrb2 , Grk2 , Grk5 cholangiocarcinoma Adrb2 , Gnas chronic obstructive pulmonary disease Adrb1 , Adrb2 Cocaine-Related Disorders Grk2 , Grk5 colitis Arrb1 Colorectal Neoplasms Gnas Congenital Abnormalities Grk2 congestive heart failure Adrb1 , Adrb2 , Arrb1 , Grk2 , Grk5 Coronary Disease Adrb2 Cushing Syndrome Gnas cystic fibrosis Adrb1 , Adrb2 dermatitis Adrb2 diabetes mellitus Adrb1 Diabetic Nephropathies Grk2 dilated cardiomyopathy Adrb1 , Adrb2 disease of cellular proliferation Gnas disease of metabolism Adrb2 drug psychosis Arrb2 Duane retraction syndrome Gnas Embryo Loss Grk2 end stage renal disease Adrb2 endocrine system disease Gnas endomyocardial fibrosis Adrb1 Experimental Arthritis Arrb1 , Arrb2 , Grk2 Experimental Autoimmune Myocarditis Grk2 Experimental Diabetes Mellitus Adrb1 Experimental Liver Cirrhosis Adrb1 , Adrb2 , Arrb2 , Grk2 Experimental Liver Neoplasms Arrb2 familial adenomatous polyposis 1 Adrb2 familial hyperlipidemia Adrb2 Familial Natural Short Sleep 2 Adrb1 Fibrosis Adrb2 Gallstones Gnas gastric adenocarcinoma Gnas genetic disease Adrb1 , Adrb2 , Arrb1 , Arrb2 , Gnas , Grk2 , Grk5 , Snx13 glioblastoma Arrb2 Graves' disease Adrb2 growth hormone secreting pituitary adenoma Gnas head and neck squamous cell carcinoma Gnas hemorrhagic disease Gnas hepatocellular carcinoma Arrb2 , Gnas Hereditary Neoplastic Syndromes Adrb2 hereditary spastic paraplegia 4 Gnas heroin dependence Arrb2 Heterotopic Ossification Gnas human immunodeficiency virus infectious disease Adrb2 Hyperalgesia Adrb1 , Grk2 Hyperemia Adrb1 hyperglycemia Adrb1 , Grk2 Hyperlipoproteinemia Type II Adrb2 hypertension Adrb1 , Adrb2 , Arrb2 , Gnas , Grk2 , Grk5 Hypertriglyceridemia Adrb2 hypokalemia Adrb2 hypothyroidism Adrb2 Hypoxia Gnas impotence Grk2 Inflammation Grk5 Insulin Resistance Adrb2 , Gnas , Grk2 intellectual disability Arrb1 , Gnas , Grk2 interstitial cystitis Adrb2 kidney disease Adrb2 Left Ventricular Hypertrophy Adrb1 , Adrb2 , Grk2 limb ischemia Grk2 liver cirrhosis Arrb1 , Arrb2 , Grk2 liver disease Grk5 Liver Injury Adrb2 low tension glaucoma Adrb1 lung adenocarcinoma Gnas lung disease Adrb2 major depressive disorder Arrb1 McCune Albright syndrome Gnas melanoma Gnas Metabolic Bone Diseases Gnas Metabolic Syndrome Adrb2 myasthenia gravis Adrb2 myocardial infarction Adrb1 , Adrb2 Myocardial Ischemia Adrb1 , Adrb2 Myocardial Reperfusion Injury Adrb1 , Adrb2 , Arrb2 , Grk2 myocarditis Adrb2 Nasal Polyps Adrb2 nephrosclerosis Adrb1 nervous system disease Adrb2 Neuralgia Grk2 neuroblastoma Gnas Neurodevelopmental Disorders Adrb2 nicotine dependence Arrb2 obesity Adrb1 , Adrb2 , Gnas obstructive lung disease Grk5 obstructive sleep apnea Adrb1 open-angle glaucoma Adrb2 opiate dependence Arrb2 , Grk2 Orthostatic Hypotension Gnas pain agnosia Arrb2 pancreatic adenocarcinoma Gnas pancreatic cancer Gnas Parasitic Liver Diseases Gnas Parkinson's disease Grk2 , Grk5 Paroxysmal Dyspnea Adrb2 periodontitis Adrb1 pituitary adenoma Grk2 pituitary adenoma 3 Gnas Pituitary Neoplasms Gnas pleomorphic xanthoastrocytoma Snx13 pneumonia Adrb2 polycystic kidney disease Gnas polycystic ovary syndrome Adrb2 , Gnas portal hypertension Arrb2 , Grk2 Precocious Puberty Gnas primary hyperaldosteronism Gnas primary open angle glaucoma Adrb2 Primary Pigmented Nodular Adrenocortical Disease, 1 Gnas progressive osseous heteroplasia Gnas Prostatic Neoplasms Adrb2 Pruritus Grk2 pseudohypoaldosteronism Gnas pseudohypoparathyroidism Gnas pseudohypoparathyroidism type IB Gnas Pseudohypoparathyroidism Type IC Gnas pseudopseudohypoparathyroidism Gnas psoriasis Adrb2 pulmonary edema Adrb2 Recurrent Infections, with Encephalopathy, Hepatic Dysfunction, and Cardiovascular Malformations Grk2 renal fibrosis Arrb2 renovascular hypertension Adrb1 Reperfusion Injury Adrb1 , Adrb2 Respiration Disorders Gnas rheumatoid arthritis Grk2 , Grk5 Right Ventricular Hypertrophy Grk2 sciatic neuropathy Adrb2 Sepsis Adrb2 , Grk2 , Grk5 sex cord-gonadal stromal tumor Gnas skin melanoma Gnas steatotic liver disease Adrb2 Stomach Neoplasms Adrb1 , Adrb2 Tachycardia Gnas Temporomandibular Joint Disorders Grk5 Tobacco Use Disorder Arrb2 toxic shock syndrome Adrb2 , Grk2 Transplant Rejection Arrb1 , Arrb2 Tremor Adrb2 type 1 diabetes mellitus Adrb1 type 2 diabetes mellitus Adrb2 , Arrb2 ulcerative colitis Adrb2 urticaria Adrb2 Uterine Cervical Neoplasms Gnas Vascular System Injuries Grk2 Ventricular Dysfunction Adrb1 Ventricular Dysfunction, Left Adrb2 Vestibulocochlear Nerve Injuries Adrb2 viral encephalitis Adrb2 withdrawal disorder Gnas