Sadashiva S. Karnik,  PhD

Sadashiva S. Karnik, PhD


Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195


  1. Regulation of physiology and pathology through AT1R in transgenic mouse models.
  2. Principlesgoverning GPCR functions through structure-function analysis of AT1R.
  3. The AT1R initiated signal transduction through application of proteomic, global gene and miRNA analysis.
  4. Genotype-phenotype relationship studies in angiotensin receptor expressing mouse models.
  5. Novel GPCR signaling paradigms through elucidation of ligand-specific signaling in AT1R.

Lay Summary

Two transmembrane signaling receptors mediate the in vivo effects of the renin angiotensin system. Of these two, the Angiotensin II (AngII) type 1 receptor (AT1R) plays an indispensable role in physiological regulation of blood pressure and water-electrolyte balance. Pathological states such as hypertension, cardiac hypertrophy and heart failure (HF) are observed when AT1R activation becomes chronic. The AT1R is a target for classical sartan-family of antihypertensive drugs. Currently these drugs are indicated for treatment of additional disease conditions such as myocardial infarction, aortic aneurism,  Marfan syndrome and diabetic nephropathy and retinopathy, which makes the sartans a target for continued drug development. AT1R is a member of G-protein coupled receptor (GPCR) family, which are transmembrane proteins that transform extracellular hormonal or physical cues into specific amplified intracellular signals.

We study all aspects of AT1R structure, function, physiology, genetics and signaling. The approaches we use include transgenesis, molecular pharmacology, ligand design, membrane protein biochemistry, protein-protein interaction, signal transduction, gene regulation, micoRNA regulation, proteomics and post-translational modifications.


  1. Significance of angiotensin 1-7 coupling with MAS1 receptor and other GPCRs to the renin-angiotensin system: IUPHAR Review 22. Karnik SS, Singh KD, Tirupula K, Unal H. Br J Pharmacol. 2017 May;174(9):737-753. doi: 10.1111/bph.13742. Epub 2017 Mar 9. Review. PMID: 28194766.
  2. Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications. Singh KD, Karnik SS. J Cell Signal. 2016 Jun;1(2). pii: 111. Epub 2016 Apr 8. PMID: 27512731.
  3. International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli. Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PM, Thomas WG. Pharmacol Rev. 2015 Oct;67(4):754-819. doi: 10.1124/pr.114.010454. Review. Erratum in: Pharmacol Rev. 2015 Oct;67(4):820. PMID: 26315714
  4. MAS C-Terminal Tail Interacting Proteins Identified by Mass Spectrometry- Based Proteomic Approach. Tirupula KC, Zhang D, Osbourne A, Chatterjee A, Desnoyer R, Willard B, Karnik SS. PLoS One. 2015 Oct 20;10(10):e0140872. doi: 10.1371/journal.pone.0140872. eCollection 2015. PMID: 26484771.
  5. G protein-coupled receptors directly bind filamin A with high affinity and promote filamin phosphorylation. Tirupula KC, Ithychanda SS, Mohan ML, Naga Prasad SV, Qin J, Karnik SS. Biochemistry. 2015 Nov 10;54(44):6673-83. doi: 10.1021/acs.biochem.5b00975. Epub 2015 Nov 2. PMID: 26460884.
  6. Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor. Zhang H, Unal H, Desnoyer R, Han GW, Patel N, Katritch V, Karnik SS, Cherezov V, Stevens RC. J Biol Chem. 2015 Dec 4;290(49):29127-39. doi: 10.1074/jbc.M115.689000. Epub 2015 Sep 29. PMID: 26420482.
  7. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor. Takezako T, Unal H, Karnik SS, Node K. Mol Pharmacol. 2015 Sep;88(3):488-501. doi: 10.1124/mol.115.099176. Epub 2015 Jun 29. PMID: 26121982.
  8. Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Zhang H, Unal H, Gati C, Han GW, Liu W, Zatsepin NA, James D, Wang D, Nelson G, Weierstall U, Sawaya MR, Xu Q, Messerschmidt M, Williams GJ, Boutet S, Yefanov OM, White TA, Wang C, Ishchenko A, Tirupula KC, Desnoyer R, Coe J, Conrad CE, Fromme P, Stevens RC, Katritch V, Karnik SS, Cherezov V. Cell. 2015 May 7;161(4):833-44. doi: 10.1016/j.cell.2015.04.011. Epub 2015 Apr 23. PMID: 25913193.
  9. Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3. Dasgupta M, Unal H, Willard B, Yang J, Karnik SS, Stark GR. J Biol Chem. 2014 Oct 31;289(44):30763-71. doi:  10.1074/jbc.M114.603894. Epub 2014 Sep 12. PMID: 25217633.
  10. Atypical signaling and functional desensitization response of MAS receptor to Peptide ligands. Tirupula KC, Desnoyer R, Speth RC, Karnik SS. PLoS ONE. 2014; 9(7): e103520. doi:10.1371/journal.pone.0103520. PMID: 25068582.
  11. Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. Kemp JR, Unal H, Desnoyer R, Yue H, Bhatnagar A, Karnik SS. J Mol Cell Cardiol. 2014; 75C:25-39. doi: 10.1016/j.yjmcc.2014.06.008. PMID: 24976017.
  12. Constitutive activity in the angiotensin II type 1 receptor: discovery and applications. Unal H, Karnik SS. Adv Pharmacol. 2014; 70:155-74. doi: 10.1016/B978-0-12-417197-8.00006-7. PMID: 24931196.
  13. Interaction of G-protein βγ complex with chromatin modulates GPCR-dependent gene regulation. Bhatnagar A, Unal H, Jagannathan R, Kaveti S, Duan ZH, Yong S, Vasanji A, Kinter M, Desnoyer R, Karnik SS. PLoS One. 2013;8(1):e52689. doi: 10.1371/journal.pone.0052689. Epub 2013 Jan 9. Erratum in: PLoS One. 2016;11(5):e0155198. PMID: 23326349.
  14. Long range effect of mutations on specific conformational changes in the extracellular loop 2 of angiotensin II type 1 receptor. Unal H, Jagannathan R, Bhatnagar A, Tirupula K, Desnoyer R, Karnik SS. J Biol Chem. 2013; 288(1):540-51. doi: 10.1074/jbc.M112.392514. PMID:23139413
  15. Mechanism of GPCR-directed autoantibodies in diseases. Unal H, Jagannathan R, Karnik SS. Adv Exp Med Biol. 2012; 749:187-99. doi: 10.1007/978-1-4614-3381-1_13. PMID: 22695846.
  16. Domain coupling in GPCRs: the engine for induced conformational changes. Unal H, Karnik SS. Trends Pharmacol Sci. 2012; 33(2):79-88. doi: 10.1016/ PMID: 22037017.
  17. AT1 receptor induced alterations in histone H2A reveal novel insights into GPCR control of chromatin remodeling. Jagannathan R, Kaveti S, Desnoyer RW, Willard B, Kinter M, Karnik SS. PLoS One. 2010; 5(9):e12552. doi: 10.1371/journal.pone.0012552. PMID: 20838438
  18. MicroRNAs--regulators of signaling networks in dilated cardiomyopathy. Naga Prasad SV, Karnik SS. J Cardiovasc Transl Res. 2010; 3(3):225-34. doi: 10.1007/s12265-010-9177-7. PMID: 20560044.
  19. Role of nuclear unphosphorylated STAT3 in angiotensin II type 1 receptor-induced cardiac hypertrophy. Yue H, Li W, Desnoyer R, Karnik SS. Cardiovasc Res. 2010; 85(1):90-9. doi: 10.1093/cvr/cvp285. PMID: 19696070.
  20. Site-specific cleavage of G protein-coupled receptor-engaged beta-arrestin. Influence of the AT1 receptor conformation on scissile site selection. Lee C, Bhatt S, Shukla A, Desnoyer RW, Yadav SP, Kim M, Jang SH, Karnik SS. J Biol Chem. 2008; 283(31):21612-20. doi: 10.1074/jbc.M803062200. PMID: 18505723.
  21. Angiotensinergic stimulation of vascular endothelium in mice causes hypotension, bradycardia, and attenuated angiotensin response. Ramchandran R, Takezako T, Saad Y, Stull L, Fink B, Yamada H, Dikalov S, Harrison DG, Moravec C, Karnik SS. Proc Natl Acad Sci U S A. 2006; 103(50):19087-92. PMID: 17148616.
  22. Multiple signaling states of G-protein-coupled receptors. Perez DM, Karnik SS. Pharmacol Rev. 2005; 57(2):147-61. PMID: 15914464.
  23. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Wei H, Ahn S, Shenoy SK, Karnik SS, Hunyady L, Luttrell LM, Lefkowitz RJ. Proc Natl Acad Sci U S A. 2003; 100(19):10782-7. PMID:12949261.
  24. Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. Miura S, Karnik SS. EMBO J. 2000; 19(15):4026-35. PMID: 10921883.
  25. Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1A angiotensin receptors. Holloway AC, Qian H, Pipolo L, Ziogas J, Miura S, Karnik S, Southwell BR, Lew MJ, Thomas WG. Mol Pharmacol. 2002; 61(4):768-77. PMID:11901215.
  26. Agonist-induced phosphorylation of the angiotensin II (AT(1A)) receptor requires generation of a conformation that is distinct from the inositol phosphate-signaling state. Thomas WG, Qian H, Chang CS, Karnik S. J Biol Chem. 2000; 275(4):2893-900. PMID:10644757.
  27. Angiotensin II type 1 and type 2 receptors bind angiotensin II through different types of epitope recognition. Miura S, Karnik SS. J Hypertens. 1999; 17(3):397-404. PMID: 10100078.
  28. Transducin-alpha C-terminal peptide binding site consists of C-D and E-F loops of rhodopsin. Acharya S, Saad Y, Karnik SS. J Biol Chem. 1997; 272(10):6519-24. PMID: 9045677.
  29. The active state of the AT1 angiotensin receptor is generated by angiotensin II induction. Noda K, Feng YH, Liu XP, Saad Y, Husain A, Karnik SS. Biochemistry. 1996; 35(51):16435-42. PMID: 8987975.
  30. Modulation of GDP release from transducin by the conserved Glu134-Arg135 sequence in rhodopsin. Acharya S, Karnik SS. J Biol Chem. 1996; 271(41):25406-11. PMID: 8810308.
  31. Angiotensin II-forming activity in a reconstructed ancestral chymase. Chandrasekharan UM, Sanker S, Glynias MJ, Karnik SS, Husain A. Science. 1996; 271(5248):502-5. PMID: 8560264.
  32. Interaction of Phe8 of angiotensin II with Lys199 and His256 of AT1 receptor in agonist activation. Noda K, Saad Y, Karnik SS. J Biol Chem. 1995; 270(48):28511-4. PMID: 7499361.
  33. Tetrazole and carboxylate groups of angiotensin receptor antagonists bind to the same subsite by different mechanisms. Noda K, Saad Y, Kinoshita A, Boyle TP, Graham RM, Husain A, Karnik SS. J Biol Chem. 270(5):2284-9. PMID: 7530721.
  34. The high affinity state of the beta 2-adrenergic receptor requires unique interaction between conserved and non-conserved extracellular loop cysteines. Noda K, Saad Y, Graham RM, Karnik SS. J Biol Chem. 1994; 269(9):6743-52. PMID: 8120034.
  35. Cysteine residues 110 and 187 are essential for the formation of correct structure in bovine rhodopsin. Karnik SS, Sakmar TP, Chen HB, Khorana HG. Proc Natl Acad Sci U S A. 1988; 85(22):8459-63. PMID: 3186735.
  36. Structure-function studies on bacteriorhodopsin. II. Improved expression of the bacterio-opsin gene in Escherichia coli. Karnik SS, Nassal M, Doi T, Jay E, Sgaramella V, Khorana HG. J Biol Chem. 1987; 262(19):9255-63. PMID: 3298253.
  37. Total synthesis of a gene for bovine rhodopsin. Ferretti L, Karnik SS, Khorana HG, Nassal M, Oprian DD. Proc Natl Acad Sci U S A. 1986; 83(3):599-603. PMID: 3456156
  38. The lysis function of RNA bacteriophage Qbeta is mediated by the maturation (A2) protein. Karnik SS, Billeter M. EMBO J. 1983; 2(9):1521-6. PMID: 11892805.
  39. Transfection of Mycobacterium smegmatis SN2 with mycobacteriophage I3 DNA. Karnik SS, Gopinathan KP. Arch Microbiol. 1983; 136(4):275-80. PMID: 6667087.
  40. Natural plant enzyme inhibitors: Part III-purification of protease inhibitors from Lathyrus sativus seeds. Bhat PG, Karnik SS, Pattabiraman TN. Indian J Biochem Biophys. 1976; 13(4):339-43. No abstract available.  PMID: 1024960.

A complete list of Dr. Karnik's publications may be viewed at PubMed.


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