1932

Abstract

This review is a somewhat chronological tale of my scientific life, emphasizing the why of the questions we asked in the lab and lessons learned that may be of value to nascent scientists. The reader will come to realize that the flow of my life has been driven by a combined life of the mind and life of the soul, intertwining like the strands of DNA.

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2022-01-06
2024-06-24
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Literature Cited

  1. 1. 
    Roe CR, Limbird LE, Wagner GS, Nerenberg ST. 1972. Isoenzyme analysis in the diagnosis of myocardial injury: application of electrophoretic methods for the detection and quantitation of the creatine phosphokinase MB isoenzyme. J. Lab. Clin. Med. 80:577–90
    [Google Scholar]
  2. 2. 
    Wagner GS, Roe CR, Limbird LE, Rosati RA, Wallace AG. 1973. The importance of identification of the myocardial-specific isoenzyme of creatine phosphokinase (MB form) in the diagnosis of acute myocardial infarction. Circulation 47:263–69
    [Google Scholar]
  3. 3. 
    Jarmakani JMM, Limbird LE, Thomas BS, Graham TC, Donald DVM et al. 1973. The effect of reestablishing coronary blood flow on the release of Creatine Phosphokinase—MB isoenzyme in experimental myocardial infarction. Am. J. Cardiol. 31:139
    [Google Scholar]
  4. 4. 
    Jarmakani JM, Limbird L, Graham TC, Marks RA. 1976. Effect of reperfusion on myocardial infarct, and the accuracy of estimating infarct size from serum creatine phosphokinase in the dog. Cardiovasc. Res. 10:245–53
    [Google Scholar]
  5. 5. 
    Dixon SH Jr., Limbird LE, Roe CR, Wagner GS, Oldham NH, Sabiston DC Jr. 1973. Recognition of postoperative acute myocardial infarction: application of isoenzyme techniques. Circulation 48:Suppl. 1137–40
    [Google Scholar]
  6. 6. 
    Limbird LE, Lefkowitz RJ. 1974. Myocardial guanylate cyclase (GC): in vivo target of acetylcholine (ACh). Circulation 50:742
    [Google Scholar]
  7. 7. 
    Limbird LE, Lefkowitz RJ. 1975. Myocardial guanylate cyclase: properties of the enzyme and effects of cholinergic agonists in vitro. Biochim. Biophys. Acta 377:185–96
    [Google Scholar]
  8. 8. 
    Lefkowitz RJ, Mukherjee C, Coverstone M, Caron MG. 1974. Stereospecific [3H](−)-alprenolol binding sites, β-adrenergic receptors and adenylate cyclase. Biochem. Biophys. Res. Commun. 60:703–9
    [Google Scholar]
  9. 9. 
    Mukherjee C, Caron MG, Coverstone M, Lefkowitz RJ. 1975. Identification of adenylate cyclase coupled β adrenergic receptors in frog erythrocytes with (−)-[3-H] alprenolol. J. Biol. Chem. 250:4869–76
    [Google Scholar]
  10. 10. 
    Sutherland EW, Robison A. 1966. The role of cyclic-3′,5′-AMP in responses to catecholamines and other hormones. Pharmacol. Rev. 18:145–61
    [Google Scholar]
  11. 11. 
    Stellwagen E, Baker B. 1976. Proposed structure for brain adenylate cyclase purified using blue dextran-Sepharose chromatography. Nature 26:719–20
    [Google Scholar]
  12. 12. 
    Limbird LE, Lefkowitz BJ. 1977. Resolution of β-adrenergic receptor binding and adenylate cyclase activity by gel exclusion chromatography. J. Biol. Chem. 252:799–802
    [Google Scholar]
  13. 13. 
    Ross EM, Gilman AG 1977. Resolution of components of adenylate cyclase. PNAS 252:6966–69
    [Google Scholar]
  14. 14. 
    Orly J, Schramm M 1976. Coupling of catecholamine receptor from one cell to another with adenylate cyclase by cell fusion. PNAS 73:4410–14
    [Google Scholar]
  15. 15. 
    Limbird LE, Lefkowitz RJ 1978. Agonist-induced increase in apparent β-adrenergic receptor size. PNAS 75:228–32
    [Google Scholar]
  16. 16. 
    Limbird LE, Gill DM, Lefkowitz RJ 1980. Agonist-promoted coupling of the β-adrenergic receptor with the guanine nucleotide regulatory protein of the adenylate cyclase system. PNAS 77:775–79
    [Google Scholar]
  17. 17. 
    Lefkowitz RJ. 2018. A serendipitous scientist. Annu. Rev. Pharmacol. Toxicol. 58:17–32
    [Google Scholar]
  18. 18. 
    Lefkowitz RJ, Hall R. 2021. A Funny Thing Happened on the Way to Stockholm: The Adrenaline-Fueled Adventures of an Accidental Scientist. New York: Pegasus
    [Google Scholar]
  19. 19. 
    Limbird LE. 2005. Cell Surface Receptors: A Short Course on Theory and Methods New York: Springer. , 3rd ed..
    [Google Scholar]
  20. 20. 
    Timmons S, Hawiger J. 1978. Separation of human platelets from plasma proteins including factor VIIIVWF by a combined albumin gradient-gel filtration method using HEPES buffer. Thromb. Res. 12:297–306
    [Google Scholar]
  21. 21. 
    Smith SK, Limbird LE. 1982. Apparent independence of the alpha-adrenergic receptor (α-AR) of the human platelet from the ADP-ribosylated 42,000 Mr subunit of the adenylate cyclase system. Fed. Proc. 41:3682
    [Google Scholar]
  22. 22. 
    Smith SK, Limbird LE 1981. Solubilization of human platelet α-adrenergic receptors: Evidence that agonist occupancy of the receptor stabilizes receptor-effector interactions. PNAS 78:4026–30
    [Google Scholar]
  23. 23. 
    Tsai BS, Lefkowitz RJ. 1978. Agonist-specific effects of monovalent and divalent cations on adenylate cyclase-coupled alpha adrenergic receptors in rabbit platelets. Mol. Pharmacol. 77:540–48
    [Google Scholar]
  24. 24. 
    Limbird LE, Speck JL, Smith SK. 1982. Sodium ion modulates agonist and antagonist interactions with the human platelet alpha2-adrenergic receptor in membrane and solubilized preparations. Mol. Pharmacol. 21:609–17
    [Google Scholar]
  25. 25. 
    Nunnari JM, Repaske MG, Brandon S, Cragoe EJ Jr., Limbird LE. 1987. Regulation of porcine brain α2-adrenergic receptors by Na+,H+ and inhibitors of Na+/H+ exchange. J. Biol. Chem. 262:12387–92
    [Google Scholar]
  26. 26. 
    Wilson AL, Guyer CA, Cragoe EJ Jr., Limbird LE. 1990. The hydrophobic tryptic core of the porcine α2-adrenergic receptor retains allosteric modulation of binding by Na+, H+, and 5-amino-substituted amiloride analogs. J. Biol. Chem. 265:17318–22
    [Google Scholar]
  27. 27. 
    Dixon RAF, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG et al. 1986. Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsin. Nature 321:75–79
    [Google Scholar]
  28. 28. 
    Spudich JL, Sineshchekov OA, Govorunova EG. 2014. Mechanism divergence in microbial rhodopsins. Biochim. Biophys. Acta Bioenerget. 1837:546–52
    [Google Scholar]
  29. 29. 
    Keefer JR, Nunnari J, Pang IH, Limbird LE. 1994. Introduction of purified alpha 2A-adrenergic receptors into uniformly oriented, unilamellar, phospholipid vesicles: productive coupling to G proteins but lack of receptor-dependent ion transport. Mol. Pharmacol. 45:12387–92
    [Google Scholar]
  30. 30. 
    Connolly TM, Limbird LE 1983. Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin. PNAS 80:5320–24
    [Google Scholar]
  31. 31. 
    Connolly TM, Limbird LE. 1983. The influence of Na+ on the α2-adrenergic receptor system of human platelets. A method for removal of extraplatelet Na+. Effect of Na+ removal on aggregation, secretion, and cAMP accumulation. J. Biol. Chem. 258:3907–12
    [Google Scholar]
  32. 32. 
    Baron BM, Limbird LE. 1988. Human platelet phospholipase A2 activity is responsive in vitro to pH and Ca2+ variations which parallel those occurring after platelet activation in vivo. Biochim. Biophys. Acta Mol. Cell Res. 971:103–11
    [Google Scholar]
  33. 33. 
    Sweatt JD, Schwartzberg MS, Frazer M, Cragoe EJ Jr., Blair IA et al. 1987. Evidence for a role for Na+-H+-exchange in activation of human platelets by PAF. Circ. Res. 61:Suppl.116–11
    [Google Scholar]
  34. 34. 
    Sweatt JD, Connolly TM, Cragoe EJ, Limbird LE. 1986. Evidence that Na+/H+ exchange regulates receptor-mediated phospholipase A2 activation in human platelets. J. Biol. Chem. 261:8667–73
    [Google Scholar]
  35. 35. 
    Sweatt JD, Johnson SL, Cragoe EJ, Limbird LE. 1985. Inhibitors of Na+/H+ exchange block stimulus-provoked arachidonic acid release in human platelets. Selective effects on platelet activation by epinephrine, ADP, and lower concentrations of thrombin. J. Biol. Chem. 260:12910–19
    [Google Scholar]
  36. 36. 
    Sweatt JD, Blair IA, Cragoe EJ, Limbird LE. 1986. Inhibitors of Na+/H+ exchange block epinephrine- and ADP-induced stimulation of human platelet phospholipase C by blockade of arachidonic acid release at a prior step. J. Biol. Chem. 261:8660–66
    [Google Scholar]
  37. 37. 
    Sweatt JD, Connolly TM, Baron BM, Limbird LE. 1988. Involvement of Na+/H+ exchange in human platelet activation. Prog. Clin. Biol. Res. 283:523–57
    [Google Scholar]
  38. 38. 
    Isom LL, Cragoe EJ Jr., Limbird LE. 1987. α2-Adrenergic receptors accelerate Na+/H+ exchange in neuroblastoma x glioma cells. J. Biol. Chem. 262:6750–67
    [Google Scholar]
  39. 39. 
    Isom LL, Cragoe EJ Jr., Limbird LE. 1987. Multiple receptors linked to inhibition of adenylate cyclase accelerate Na+/H+ exchange in neuroblastoma x glioma cells via a mechanism other than decreased cAMP accumulation. J. Biol. Chem. 262:17504–9
    [Google Scholar]
  40. 40. 
    Esser V, Limbird LE, Brown MS, Goldstein JL, Russell DW. 1988. Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J. Biol. Chem. 263:13282–91
    [Google Scholar]
  41. 41. 
    Liu W, Chun E, Thompson AA, Chubukov P, Xu F et al. 2012. Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337:232–36
    [Google Scholar]
  42. 42. 
    Limbird LE. 1988. Receptors linked to inhibition of adenylate cyclase: additional signaling mechanisms. FASEB J 2:2686–95
    [Google Scholar]
  43. 43. 
    Surprenant A, Horstman DA, Akbarali H, Limbird LE. 1992. A point mutation of the alpha 2-adrenoceptor that blocks coupling to potassium but not calcium currents. Science 257:977–80
    [Google Scholar]
  44. 44. 
    MacMillan LB, Hein L, Smith MS, Piascik MT, Limbird LE. 1996. Central hypotensive effects of the α2a-adrenergic receptor subtype. Science 273:801–3
    [Google Scholar]
  45. 45. 
    Wilson MH, Limbird LE. 2000. Mechanisms regulating the cell surface residence time of the α2A-adrenergic receptor. Biochemistry 39:693–700
    [Google Scholar]
  46. 46. 
    Wilson MH, Highfield HA, Limbird LE. 2001. The role of a conserved inter-transmembrane domain interface in regulating α2-adrenergic receptor conformational stability and cell-surface turnover. Mol. Pharmacol. 59:929–38
    [Google Scholar]
  47. 47. 
    Hein L, Limbird LE, Eglen RM, Kobilka BK. 1999. Gene substitution/knockout to delineate the role of α2-adrenoceptor subtypes in mediating central effects of catecholamines and imidazolines. Ann. N. Y. Acad. Sci. 881:265–71
    [Google Scholar]
  48. 48. 
    Lakhlani PP, MacMillan LB, Guo TZ, McCool BA, Lovinger DM et al. 1997. Substitution of a mutant α2a-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. PNAS 94:9950–55
    [Google Scholar]
  49. 49. 
    Schramm NL, McDonald MP, Limbird LE. 2001. The α2-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J. Neurosci. 21:4875–82
    [Google Scholar]
  50. 50. 
    Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL. 1997. The α2a adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic-opioid synergy. J. Neurosci. 17:7157–65
    [Google Scholar]
  51. 51. 
    Janumpalli S, Butler LS, MacMillan LB, Limbird LE, McNamara JO. 1998. A point mutation (D79N) of the α2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine. J. Neurosci. 18:2004–8
    [Google Scholar]
  52. 52. 
    Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF. 2002. Mutation of the α2-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J. Neurosci. 22:8771–77
    [Google Scholar]
  53. 53. 
    Gomeza J, Shannon H, Kostenis E, Felder C, Zhang L et al. 1999. Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice. PNAS 96:1692–97
    [Google Scholar]
  54. 54. 
    Tan CM, Wilson MH, MacMillan LB, Kobilka BK, Limbird LE 2002. Heterozygous α2-adrenergic receptor mice unveil unique therapeutic benefits of partial agonists. PNAS 99:12471–76
    [Google Scholar]
  55. 55. 
    Arnsten AFT, Cai JX, Goldman-Rakic PS. 1988. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J. Neurosci. 8:4287–98
    [Google Scholar]
  56. 56. 
    Violin JD, Lefkowitz RJ. 2007. β-Arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28:416–22
    [Google Scholar]
  57. 57. 
    Shukla AK, Singh G, Ghosh E. 2014. Emerging structural insights into biased GPCR signaling. Trends Biochem. Sci. 39:12594–602
    [Google Scholar]
  58. 58. 
    Stallaert W, Christopoulos A, Bouvier M. 2011. Ligand functional selectivity and quantitative pharmacology at G protein-coupled receptors. Expert Opin. Drug Discov. 6:8811–25
    [Google Scholar]
  59. 59. 
    Keefer JR, Limbird LE. 1993. The alpha 2A-adrenergic receptor is targeted directly to the basolateral membrane domain of Madin-Darby canine kidney cells independent of coupling to pertussis toxin-sensitive GTP-binding proteins. J. Biol. Chem. 268:8003–11
    [Google Scholar]
  60. 60. 
    Wozniak M, Limbird LE. 1996. The three α2-adrenergic receptor subtypes achieve basolateral localization in Madin-Darby canine kidney II cells via different targeting mechanisms. J. Biol. Chem. 271:5017–24
    [Google Scholar]
  61. 61. 
    Brady AE, Limbird LE. 2002. G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction. Cell. Signal. 14:297–309
    [Google Scholar]
  62. 62. 
    Keefer JR, Kennedy ME, Limbird LE. 1994. Unique structural features important for stabilization versus polarization of the α2A-adrenergic receptor on the basolateral membrane of Madin-Darby canine kidney cells. J. Biol. Chem. 269:16425–32
    [Google Scholar]
  63. 63. 
    Edwards SW, Limbird LE. 1999. Role for the third intracellular loop in cell surface stabilization of the α2A-adrenergic receptor. J. Biol. Chem. 274:16331–36
    [Google Scholar]
  64. 64. 
    Prezeau L, Richman JG, Edwards SW, Limbird LE. 1999. The ζ isoform of 14-3-3 proteins interacts with the third intracellular loop of different α2-adrenergic receptor subtypes. J. Biol. Chem. 274:13462–69
    [Google Scholar]
  65. 65. 
    Brady AE, Wang Q, Colbran RJ, Allen PB, Greengard P, Limbird LE. 2003. Spinophilin stabilizes cell surface expression of α2-adrenergic receptors. J. Biol. Chem. 278:32405–12
    [Google Scholar]
  66. 66. 
    Richman JGG, Brady AE, Wang Q, Hensel JL, Colbran RJ, Limbird LE. 2001. Agonist-regulated interaction between α2 adrenergic receptors and spinophilin. J. Biol. Chem. 276:15003–8
    [Google Scholar]
  67. 67. 
    Wang Q, Limbird LE. 2002. Regulated interactions of the α2A adrenergic receptor with spinophilin, 14-3-3ζ, and arrestin 3. J. Biol. Chem. 277:50589–96
    [Google Scholar]
  68. 68. 
    Wang Q, Zhao J, Brady AE, Feng J, Allen PB, Greengard P, Limbird LE. 2004. Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors. Science 304:1940–44
    [Google Scholar]
  69. 69. 
    Shenoy SK, Lefkowitz RJ. 2011. β-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol. Sci. 32:521–33
    [Google Scholar]
  70. 70. 
    Dweck C. 2017. Mindset: Changing the Way You Think to Fulfil Your Potential London: Constable & Robinson
    [Google Scholar]
  71. 71. 
    Dweck CS, Yeager DS. 2019. Mindsets: a view from two eras. Perspect. Psychol. Sci. 14:481–96
    [Google Scholar]
  72. 72. 
    Oliver M. 1990. House of Light Boston: Beacon Press
    [Google Scholar]
  73. 73. 
    Hannah-Jones N. 2020. What is owed. It is time for reparations. The New York Times Magazine June 4. https://www.nytimes.com/interactive/2020/06/24/magazine/reparations-slavery.html
    [Google Scholar]
  74. 74. 
    Coates T-N. 2014. The case for reparations. The Atlantic May 22. https://www.theatlantic.com/magazine/archive/2014/06/the-case-for-reparations/361631/
    [Google Scholar]
  75. 75. 
    Richardson HC. 2020. How the South Won the Civil War: Oligarchy, Democracy, and the Continuing Fight for the Soul of America New York: Oxford Univ. Press
    [Google Scholar]
  76. 76. 
    Favors J. 2019. Shelter in a Time of Storm: How Black Colleges Fostered Generations of Leadership and Activism. Chapel Hill: Univ North Carolina Press
    [Google Scholar]
  77. 77. 
    Kendi IX. 2019. How to Be an Antiracist New York: One World
    [Google Scholar]
  78. 78. 
    McGhee H. 2021. The Sum of Us: What Racism Costs Everyone and How We Can Prosper Together New York: Penguin
    [Google Scholar]
  79. 79. 
    Torino GC, Rivera DP, Capodilupa CW, Nadal KL, Sue DW 2018. Microaggression Theory: Influence and Implications Hoboken, NJ: Wiley
    [Google Scholar]
  80. 80. 
    Pittman CT. 2012. Racial microaggressions: the narratives of African American faculty at a predominantly white university. J. Negro Educ. 81:82–92
    [Google Scholar]
  81. 81. 
    Hughes L. 1990 (1933. The Ways of White Folks New York: Vintage Classics
    [Google Scholar]
  82. 82. 
    DuBois WEB. 1903. The Souls of Black Folk Chicago: A.G. McClurg
    [Google Scholar]
  83. 83. 
    Montgomery BL. 2018. From deficits to possibilities: mentoring lessons from plants. Public Philos. J. 1:1–12
    [Google Scholar]
  84. 84. 
    Whittaker JA, Montgomery BL. 2012. Cultivating diversity and competency in STEM: Challenges and remedies for removing virtual barriers to constructing diverse higher education communities of success. J. Undergrad. Neurosci. Educ. 11:A44–51
    [Google Scholar]
  85. 85. 
    Montgomery BL, Dodson JE, Johnson SM. 2014. Guiding the way: mentoring graduate students and junior faculty for sustainable academic careers. SAGE Open 4:471–76
    [Google Scholar]
  86. 86. 
    Natl. Cent. Educ. Stat. (NCES) 2020. Graduate degree fields Rep., NCES, US Dep. Educ. Washington, DC: https://nces.ed.gov/programs/coe/indicator_ctb.asp
    [Google Scholar]
  87. 87. 
    Schiebner N. 1969. Untitled poem. Hillary Rodham's Student Commencement Speech Wellesley College Wellesley, MA: https://www.wellesley.edu/events/commencement/archives/1969commencement/studentspeech
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