Mechanism of GPCR-Directed Autoantibodies in Diseases

  • Hamiyet Unal
  • Rajaganapathi Jagannathan
  • Sadashiva S. Karnik
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (volume 749)


Receptor-activating autoantibodies targeting different G-protein-coupled receptors (GPCRs) have been discovered that exhibit agonist-like activity in several human pathologies. For example, autoimmune pathogenesis of Graves’ disease is attributed to autoantibody-mediated activation of the thyrotropin receptor, a GPCR. Likewise, diseases such as preeclampsia and vascular allograft rejection are caused by autoantibodies against angiotensin II type 1 receptor (AT1R). The serum of patients with Chagas disease causing congestive heart failure contains an autoantibody for the β1-adrenergic receptor. Autoantibodies against α1- and β1- and β2-adrenergic receptors found in serum from patients are linked to malignant hypertension and idiopathic dilated cardiomyopathy, respectively. Additional examples of GPCR-activating antibodies include those against the mGluR, GABA, 5HT4, calcium-sensing receptor, muscarinic M1 and M2 receptors, which have been identified in various chronic neurological diseases patients. The GPCR-directed autoantibodies may actually initiate the cellular signaling responsible for the disease since each disorder is associated with a specific GPCR-directed autoantibody. Empirical evidence suggests that the autoantibody induces GPCR activation without the endogenous ligand; however, the mechanism of antibody mediated receptor activation is not known. We show that the conformational dynamics of the extracellular domain of the AT1R generates the epitope for an autoantibody on the plasma membrane surface. This allows the antibody to bind and stabilize the activated state of AT1R, thus providing a molecular basis for the autoantibody action.


Purkinje Cell Disulfide Bond Idiopathic Dilate Cardiomyopathy Congenital Heart Block GPCR Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank members of SK-lab for fruitful discussions and advice. The work was supported by NRSA award to H.U. (HL007914) and RO1 grants (HL57470 and HL83243) to S.K.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hamiyet Unal
    • 1
  • Rajaganapathi Jagannathan
    • 1
  • Sadashiva S. Karnik
    • 1
  1. 1.Department of Molecular CardiologyLerner Research Institute, Cleveland Clinic FoundationClevelandUSA

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