My work is focused on understanding the molecular basis of signaling mechanisms mediated by G proteins, which are switch proteins. G proteins are normally inactive, but a receptor that has received a specific signal can activate G proteins, leading to changes in the activity of enzymes that produce second messengers such as cyclic AMP and calcium.

The resulting changes in cellular activity underlie a large number of physiological processes. G protein-mediated signalling cascades are key regulators of many physiological processes, including processes of development, differentiation, and regulation of cell division. In the brain, many key neurotransmitters and neuromodulators mediate a myriad of functions by activation of such G protein cascades.

The research in my laboratory is aimed at understanding how G proteins become activated by receptors, how they in turn activate effector enzymes, and how they turn off. We determined the sites of interaction between proteins using a method of decomposing the proteins into small synthetic peptides and determining which peptides blocked interaction sites (Hamm et al., 1988; Rarick et al., 1992; Artemyev et al., 1993; Arshavsky et al., 1994). To understand the process more fully, we determined the atomic structure of the proteins in collaboration with the group of Paul Sigler. We used X-ray crystallography to solve the three-dimensional structures of G proteins in their inactive (GDP bound, (Lambright et al., 1994) and activated (GTPbgS-bound) forms (Noel et al., 1993). We caught a glimpse of the self-inactivating process in another crystal form, the transition state analog, Ga.GDP.AlF4- (Sondek et al., 1994). More recently, the structures of the bg subunit (Sondek et al., 1996) and the heterotrimeric G protein (Lambright et al., 1996) were solved. These high-resolution structural studies allowed us to postulate specific hypotheses regarding mechanisms of receptor:G protein interaction and activation, G protein subunit association-dissociation and effector activation.


The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Author Correction: The in vivo specificity of synaptic Gβ and Gγ subunits to the α adrenergic receptor at CNS synapses. Yim YY, Betke KM, McDonald WH, Gilsbach R, Chen Y, Hyde K, Wang Q, Hein L, Hamm HE (2020) Sci Rep 10(1): 2966
    › Primary publication · 32060295 (PubMed) · PMC7021690 (PubMed Central)
  2. Heterosynaptic GABA Receptor Function within Feedforward Microcircuits Gates Glutamatergic Transmission in the Nucleus Accumbens Core. Manz KM, Baxley AG, Zurawski Z, Hamm HE, Grueter BA (2019) J Neurosci 39(47): 9277-9293
    › Primary publication · 31578230 (PubMed) · PMC6867813 (PubMed Central)
  3. Physiological roles for neuromodulation via G GPCRs working through Gβγ-SNARE interaction. Hamm HE, Alford ST (2020) Neuropsychopharmacology 45(1): 221
    › Primary publication · 31477818 (PubMed) · PMC6879731 (PubMed Central)
  4. Disabling Gβγ-SNAP-25 interaction in gene-targeted mice results in enhancement of long-term potentiation at Schaffer collateral-CA1 synapses in the hippocampus. Irfan M, Zurawski Z, Hamm HE, Bark C, Stanton PK (2019) Neuroreport 30(10): 695-699
    › Primary publication · 31095110 (PubMed) · PMC7768948 (PubMed Central)
  5. Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes. Zurawski Z, Thompson Gray AD, Brady LJ, Page B, Church E, Harris NA, Dohn MR, Yim YY, Hyde K, Mortlock DP, Jones CK, Winder DG, Alford S, Hamm HE (2019) Sci Signal 12(569)
    › Primary publication · 30783011 (PubMed) · PMC7758873 (PubMed Central)
  6. The in vivo specificity of synaptic Gβ and Gγ subunits to the α adrenergic receptor at CNS synapses. Yim YY, Betke KM, McDonald WH, Gilsbach R, Chen Y, Hyde K, Wang Q, Hein L, Hamm HE (2019) Sci Rep 9(1): 1718
    › Primary publication · 30737458 (PubMed) · PMC6368627 (PubMed Central)
  7. The expanding roles and mechanisms of G protein-mediated presynaptic inhibition. Zurawski Z, Yim YY, Alford S, Hamm HE (2019) J Biol Chem 294(5): 1661-1670
    › Primary publication · 30710014 (PubMed) · PMC6364771 (PubMed Central)
  8. Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. Rigg RA, Healy LD, Chu TT, Ngo ATP, Mitrugno A, Zilberman-Rudenko J, Aslan JE, Hinds MT, Vecchiarelli LD, Morgan TK, Gruber A, Temple KJ, Lindsley CW, Duvernay MT, Hamm HE, McCarty OJT (2019) Platelets 30(1): 126-135
    › Primary publication · 30560697 (PubMed) · PMC6397092 (PubMed Central)
  9. The role of coagulation and platelets in colon cancer-associated thrombosis. Mitrugno A, Tassi Yunga S, Sylman JL, Zilberman-Rudenko J, Shirai T, Hebert JF, Kayton R, Zhang Y, Nan X, Shatzel JJ, Esener S, Duvernay MT, Hamm HE, Gruber A, Williams CD, Takata Y, Armstrong R, Morgan TK, McCarty OJT (2019) Am J Physiol Cell Physiol 316(2): C264-C273
    › Primary publication · 30462538 (PubMed) · PMC6397342 (PubMed Central)
  10. Tracing the evolution of the heterotrimeric G protein α subunit in Metazoa. Lokits AD, Indrischek H, Meiler J, Hamm HE, Stadler PF (2018) BMC Evol Biol 18(1): 51
    › Primary publication · 29642851 (PubMed) · PMC5896119 (PubMed Central)
  11. GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation. Damian M, Pons V, Renault P, M'Kadmi C, Delort B, Hartmann L, Kaya AI, Louet M, Gagne D, Ben Haj Salah K, Denoyelle S, Ferry G, Boutin JA, Wagner R, Fehrentz JA, Martinez J, Marie J, Floquet N, Galès C, Mary S, Hamm HE, Banères JL (2018) Proc Natl Acad Sci U S A 115(17): 4501-4506
    › Primary publication · 29632174 (PubMed) · PMC5924877 (PubMed Central)
  12. G Protein Preassembly Rescues Efficacy of W Toggle Mutations in Neuropeptide Y Receptor. Kaiser A, Hempel C, Wanka L, Schubert M, Hamm HE, Beck-Sickinger AG (2018) Mol Pharmacol 93(4): 387-401
    › Primary publication · 29436493 (PubMed)
  13. Improved Folding of the Y G Protein-Coupled Receptor into Bicelles. Schmidt P, Bender BJ, Kaiser A, Gulati K, Scheidt HA, Hamm HE, Meiler J, Beck-Sickinger AG, Huster D (2017) Front Mol Biosci : 100
    › Primary publication · 29387686 (PubMed) · PMC5776092 (PubMed Central)
  14. Quantitative Multiple-Reaction Monitoring Proteomic Analysis of Gβ and Gγ Subunits in C57Bl6/J Brain Synaptosomes. Yim YY, McDonald WH, Hyde K, Cruz-Rodríguez O, Tesmer JJG, Hamm HE (2017) Biochemistry 56(40): 5405-5416
    › Primary publication · 28880079 (PubMed) · PMC5769682 (PubMed Central)
  15. Gβγ directly modulates vesicle fusion by competing with synaptotagmin for binding to neuronal SNARE proteins embedded in membranes. Zurawski Z, Page B, Chicka MC, Brindley RL, Wells CA, Preininger AM, Hyde K, Gilbert JA, Cruz-Rodriguez O, Currie KPM, Chapman ER, Alford S, Hamm HE (2017) J Biol Chem 292(29): 12165-12177
    › Primary publication · 28515322 (PubMed) · PMC5519367 (PubMed Central)
  16. A Presynaptic Group III mGluR Recruits Gβγ/SNARE Interactions to Inhibit Synaptic Transmission by Cone Photoreceptors in the Vertebrate Retina. Van Hook MJ, Babai N, Zurawski Z, Yim YY, Hamm HE, Thoreson WB (2017) J Neurosci 37(17): 4618-4634
    › Primary publication · 28363980 (PubMed) · PMC5413191 (PubMed Central)
  17. Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets. Duvernay MT, Temple KJ, Maeng JG, Blobaum AL, Stauffer SR, Lindsley CW, Hamm HE (2017) Mol Pharmacol 91(1): 39-47
    › Primary publication · 27784794 (PubMed) · PMC5198515 (PubMed Central)
  18. Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles. Temple KJ, Duvernay MT, Maeng JG, Blobaum AL, Stauffer SR, Hamm HE, Lindsley CW (2016) Bioorg Med Chem Lett 26(22): 5481-5486
    › Primary publication · 27777004 (PubMed) · PMC5340293 (PubMed Central)
  19. Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin. Temple KJ, Duvernay MT, Young SE, Wen W, Wu W, Maeng JG, Blobaum AL, Stauffer SR, Hamm HE, Lindsley CW (2016) J Med Chem 59(16): 7690-5
    › Primary publication · 27482618 (PubMed) · PMC5775816 (PubMed Central)
  20. A Conserved Hydrophobic Core in Gαi1 Regulates G Protein Activation and Release from Activated Receptor. Kaya AI, Lokits AD, Gilbert JA, Iverson TM, Meiler J, Hamm HE (2016) J Biol Chem 291(37): 19674-86
    › Primary publication · 27462082 (PubMed) · PMC5016700 (PubMed Central)
  21. Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor. Oliver KH, Duvernay MT, Hamm HE, Carneiro AM (2016) J Biol Chem 291(38): 20210-9
    › Primary publication · 27422820 (PubMed) · PMC5025703 (PubMed Central)
  22. Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity. Gupta A, Gomes I, Bobeck EN, Fakira AK, Massaro NP, Sharma I, Cavé A, Hamm HE, Parello J, Devi LA (2016) Proc Natl Acad Sci U S A 113(21): 6041-6
    › Primary publication · 27162327 (PubMed) · PMC4889365 (PubMed Central)
  23. Gβγ Binds to the Extreme C Terminus of SNAP25 to Mediate the Action of Gi/o-Coupled G Protein-Coupled Receptors. Zurawski Z, Rodriguez S, Hyde K, Alford S, Hamm HE (2016) Mol Pharmacol 89(1): 75-83
    › Primary publication · 26519224 (PubMed) · PMC4702098 (PubMed Central)
  24. Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention. Friedman EA, Texeira L, Delaney J, Weeke PE, Lynch DR, Kasasbeh E, Song Y, Harrell FE, Denny JC, Hamm HE, Roden DM, Cleator JH (2016) J Thromb Thrombolysis 41(4): 656-62
    › Primary publication · 26446588 (PubMed)
  25. Platelet Lipidomic Profiling: Novel Insight into Cytosolic Phospholipase A2α Activity and Its Role in Human Platelet Activation. Duvernay MT, Matafonov A, Lindsley CW, Hamm HE (2015) Biochemistry 54(36): 5578-88
    › Primary publication · 26295742 (PubMed) · PMC7748375 (PubMed Central)
  26. Functional stability of rhodopsin in a bicelle system: evaluating G protein activation by rhodopsin in bicelles. Kaya AI, Iverson TM, Hamm HE (2015) Methods Mol Biol : 67-76
    › Primary publication · 25697517 (PubMed)
  27. The hyperglycemic byproduct methylglyoxal impairs anticoagulant activity through covalent adduction of antithrombin III. Jacobson R, Mignemi N, Rose K, O'Rear L, Sarilla S, Hamm HE, Barnett JV, Verhamme IM, Schoenecker J (2014) Thromb Res 134(6): 1350-7
    › Primary publication · 25307422 (PubMed) · PMC4337957 (PubMed Central)
  28. Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354. Wen W, Young SE, Duvernay MT, Schulte ML, Nance KD, Melancon BJ, Engers J, Locuson CW, Wood MR, Daniels JS, Wu W, Lindsley CW, Hamm HE, Stauffer SR (2014) Bioorg Med Chem Lett 24(19): 4708-4713
    › Primary publication · 25176330 (PubMed) · PMC5716344 (PubMed Central)
  29. Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects. Cleator JH, Duvernay MT, Holinstat M, Colowick NE, Hudson WJ, Song Y, Harrell FE, Hamm HE (2014) J Pharmacol Exp Ther 351(1): 33-43
    › Primary publication · 25052834 (PubMed) · PMC4165026 (PubMed Central)
  30. A conserved phenylalanine as a relay between the α5 helix and the GDP binding region of heterotrimeric Gi protein α subunit. Kaya AI, Lokits AD, Gilbert JA, Iverson TM, Meiler J, Hamm HE (2014) J Biol Chem 289(35): 24475-87
    › Primary publication · 25037222 (PubMed) · PMC4148873 (PubMed Central)
  31. A transient interaction between the phosphate binding loop and switch I contributes to the allosteric network between receptor and nucleotide in Gαi1. Thaker TM, Sarwar M, Preininger AM, Hamm HE, Iverson TM (2014) J Biol Chem 289(16): 11331-11341
    › Primary publication · 24596087 (PubMed) · PMC4036270 (PubMed Central)
  32. Differential localization of G protein βγ subunits. Betke KM, Rose KL, Friedman DB, Baucum AJ, Hyde K, Schey KL, Hamm HE (2014) Biochemistry 53(14): 2329-43
    › Primary publication · 24568373 (PubMed) · PMC4004276 (PubMed Central)
  33. Modulation of neurotransmission by GPCRs is dependent upon the microarchitecture of the primed vesicle complex. Hamid E, Church E, Wells CA, Zurawski Z, Hamm HE, Alford S (2014) J Neurosci 34(1): 260-74
    › Primary publication · 24381287 (PubMed) · PMC3866488 (PubMed Central)
  34. Energetic analysis of the rhodopsin-G-protein complex links the α5 helix to GDP release. Alexander NS, Preininger AM, Kaya AI, Stein RA, Hamm HE, Meiler J (2014) Nat Struct Mol Biol 21(1): 56-63
    › Primary publication · 24292645 (PubMed) · PMC3947367 (PubMed Central)
  35. G-protein-coupled receptors: evolving views on physiological signalling: symposium on G-protein-coupled receptors: evolving concepts and new techniques. Holinstat M, Oldham WM, Hamm HE (2006) EMBO Rep 7(9): 866-9
    › Primary publication · 16906127 (PubMed) · PMC1559677 (PubMed Central)
  36. Direct modulation of phospholipase D activity by Gbetagamma. Preininger AM, Henage LG, Oldham WM, Yoon EJ, Hamm HE, Brown HA (2006) Mol Pharmacol 70(1): 311-8
    › Primary publication · 16638972 (PubMed)
  37. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Cleator JH, Zhu WQ, Vaughan DE, Hamm HE (2006) Blood 107(7): 2736-44
    › Primary publication · 16332977 (PubMed) · PMC1895372 (PubMed Central)
  38. G betagamma binds histone deacetylase 5 (HDAC5) and inhibits its transcriptional co-repression activity. Spiegelberg BD, Hamm HE (2005) J Biol Chem 280(50): 41769-76
    › Primary publication · 16221676 (PubMed)
  39. RACK1 binds to a signal transfer region of G betagamma and inhibits phospholipase C beta2 activation. Chen S, Lin F, Hamm HE (2005) J Biol Chem 280(39): 33445-52
    › Primary publication · 16051595 (PubMed)
  40. RACK1 regulates specific functions of Gbetagamma. Chen S, Dell EJ, Lin F, Sai J, Hamm HE (2004) J Biol Chem 279(17): 17861-8
    › Primary publication · 14963031 (PubMed)
  41. An intramolecular contact in Galpha transducin that participates in maintaining its intrinsic GDP release rate. Thomas TO, Bae H, Medkova M, Hamm HE (2001) Mol Cell Biol Res Commun 4(5): 282-91
    › Primary publication · 11529678 (PubMed)
  42. Modulation of the G protein regulator phosducin by Ca2+/calmodulin-dependent protein kinase II phosphorylation and 14-3-3 protein binding. Thulin CD, Savage JR, McLaughlin JN, Truscott SM, Old WM, Ahn NG, Resing KA, Hamm HE, Bitensky MW, Willardson BM (2001) J Biol Chem 276(26): 23805-15
    › Primary publication · 11331285 (PubMed)
  43. How activated receptors couple to G proteins. Hamm HE (2001) Proc Natl Acad Sci U S A 98(9): 4819-21
    › Primary publication · 11320227 (PubMed) · PMC33117 (PubMed Central)