Professor of Physiology and Membrane Biology
Neurobiology of addictive disorders and their comorbidities
The majority of drugs used in human medicine target G protein coupled receptors (GPCRs). The focus in the Whistler laboratory is elucidating how altering the signaling “bias” of a GPCR for its various downstream signaling partners contributes to drug responsiveness and side effect profile.
Dr. Whistler is particularly interested in the role of biased versus balanced GPCR signaling in modulating responsiveness to drugs of abuse and the co-morbidities of anxiety, depression and altered decision making that accompany drug use/abuse. Starting with the opioid receptors, the laboratory demonstrated the in vivo relevance of altered signaling bias in addiction disorders. Specifically, her team demonstrated that altering the signaling bias of morphine so that it mimicked that of endorphin, one of our body’s endogenous opioids, could prevent the development of tolerance, dependence and addiction to this drug without adversely affecting analgesia.
They have since extended these studies to other clinically important GPCR targets and their ligands/drugs that are important for the treatment of psychosis, depression, Parkinson’s disease, anxiety, asthma and metabolic disease. These receptors, including the dopamine receptors and the incretin receptors, and the clinically important drugs that target them, are, as yet, poorly characterize for their signaling bias. The Labs future goals follow four main paths: 1) They are determining the changes in the brain that are responsible for addiction to opioid drugs 2) They are optimizing and providing preclinical in vivo data to stimulate the clinical development of a “balanced” opioid analgesic with reduced abuse liability. 3) They are examining a number of other clinically important GPCR drugs for their signaling bias, and evaluating the consequences of altering their bias. 4) They are determining whether naturally occurring genetic variation at clinically important GPCR targets in the human population affects signaling bias in response to endogenous ligand and clinically important drugs that target these receptors.
Work in Dr. Whistler's laboratory spans many disciplines, including cell biology, pharmacology, biochemistry, genetics, electrophysiology and complex animal behavior. She is always searching for talented postdoctoral fellows and students to join her team.
Grad Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
Specialties / Focus
- Cellular and Molecular Neurobiology
- Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins. Johnson TA, Milan-Lobo L, Che T, Ferwerda M, Lambu E, McIntosh NL, Li F, He L, Lorig-Roach N, Crews P, Whistler JL. ACS Chemical Neuroscience. 2017; 8(3):473-485. NIHMSID: NIHMS836716 PubMed [journal]PMID: 27744679 PMCID: PMC5352491
- β-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment. Yang S, Ben-Shalom R, Ahn M, Liptak AT, van Rijn RM, Whistler JL, Bender KJ. Cell Reports. 2016; 16(6):1518-1526. NIHMSID: NIHMS801162 PubMed [journal]PMID: 27452469 PMCID: PMC5074334
- TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning. Luo SX, Timbang L, Kim JI, Shang Y, Sandoval K, Tang AA, Whistler JL, Ding JB, Huang EJ. Cell Reports. 2016; 17(12):3233-3245. NIHMSID: NIHMS832472 PubMed [journal]PMID: 28009292 PMCID: PMC5312261
- Real-time trafficking and signaling of the glucagon-like peptide-1 receptor. Roed SN, Wismann P, Underwood CR, Kulahin N, Iversen H, Cappelen KA, Schäffer L, Lehtonen J, Hecksher-Soerensen J, Secher A, Mathiesen JM, Bräuner-Osborne H, Whistler JL, Knudsen SM, Waldhoer M. Molecular and cellular endocrinology. 2014; 382(2):938-49.
- Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area. Madhavan A, Argilli E, Bonci A, Whistler JL. The Journal of Neuroscience. 2013; 33(30):12329-36. PubMed [journal]PMID: 23884939 PMCID: PMC3721842
- Anti-analgesic effect of the mu/delta opioid receptor heteromer revealed by ligand-biased antagonism. Milan-Lobo L, Enquist J, van Rijn RM, Whistler JL. PloS One. 2013; 8(3):e58362. PubMed [journal]PMID: 23554887 PMCID: PMC3598907
- Chronic ethanol potentiates the effect of neuropeptide s in the basolateral amygdala and shows increased anxiolytic and anti-depressive effects. Enquist J, Ferwerda M, Madhavan A, Hok D, Whistler JL. Neuropsychopharmacology. 2012; 37(11):2436-45. PubMed [journal]PMID: 22739468 PMCID: PMC3445991
- Tuned-Affinity Bivalent Ligands for the Characterization of Opioid Receptor Heteromers. Harvey JH, Long DH, England PM, Whistler JL. ACS medicinal chemistry letters. 2012; 3(8):640-644. NIHMSID: NIHMS395014 PubMed [journal]PMID: 23585918 PMCID: PMC3622216
- Emergence of functional spinal delta opioid receptors after chronic ethanol exposure. van Rijn RM, Brissett DI, Whistler JL. Biological Psychiatry. 2012; 71(3):232-8. NIHMSID: NIHMS330233 PubMed [journal]PMID: 21889123 PMCID: PMC4086708
- Morphine-induced mu opioid receptor trafficking enhances reward yet prevents compulsive drug use. Berger AC, Whistler JL. EMBO Molecular Medicine. 2011; 3(7):385-97. PubMed [journal]PMID: 21656686 PMCID: PMC3394511
- Opioid-Induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area. Madhavan A, Bonci A, Whistler JL. The Journal of Neuroscience. 2010; 30(42):14029-35. NIHMSID: NIHMS246495 PubMed [journal]PMID: 20962224 PMCID: PMC3637958
- Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine. Thompson D, Martini L, Whistler JL. PloS One. 2010; 5(6):e11038. PubMed [journal]PMID: 20543951 PMCID: PMC2882949
- Dual efficacy of delta opioid receptor-selective ligands for ethanol drinking and anxiety. van Rijn RM, Brissett DI, Whistler JL. The Journal of Pharmacology and Experimental Therapeutics. 2010; 335(1):133-9. PubMed [journal]PMID: 20605909 PMCID: PMC2957775
- Chronic ethanol consumption in rats produces opioid antinociceptive tolerance through inhibition of mu opioid receptor endocytosis. He L, Whistler JL. PloS One. 2011; 6(5):e19372. PubMed [journal]PMID: 21602922 PMCID: PMC3094338
- micro-Opioid receptor endocytosis prevents adaptations in ventral tegmental area GABA transmission induced during naloxone-precipitated morphine withdrawal. Madhavan A, He L, Stuber GD, Bonci A, Whistler JL. The Journal of Neuroscience. 2010; 30(9):3276-86. NIHMSID: NIHMS228217 PubMed [journal]PMID: 20203187 PMCID: PMC2943338
- The delta(1) opioid receptor is a heterodimer that opposes the actions of the delta(2) receptor on alcohol intake. van Rijn RM, Whistler JL. Biological Psychiatry. 2009; 66(8):777-84. NIHMSID: NIHMS130266 PubMed [journal]PMID: 19576572 PMCID: PMC2757485
- Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Kim JA, Bartlett S, He L, Nielsen CK, Chang AM, Kharazia V, Waldhoer M, Ou CJ, Taylor S, Ferwerda M, Cado D, Whistler JL. Current Biology : CB. 2008; 18(2):129-35. NIHMSID: NIHMS38997 PubMed [journal]PMID: 18207746 PMCID: PMC2997702
- A molecular basis of analgesic tolerance to cannabinoids. Tappe-Theodor A, Agarwal N, Katona I, Rubino T, Martini L, Swiercz J, Mackie K, Monyer H, Parolaro D, Whistler J, Kuner T, Kuner R. The Journal of Neuroscience. 2007; 27(15):4165-77. PubMed [journal]PMID: 17428994
- Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. Martini L, Waldhoer M, Pusch M, Kharazia V, Fong J, Lee JH, Freissmuth C, Whistler JL. FASEB Journal. 2007; 21(3):802-11. PubMed [journal]PMID: 17197383
- Dopamine responsiveness is regulated by targeted sorting of D2 receptors. Bartlett SE, Enquist J, Hopf FW, Lee JH, Gladher F, Kharazia V, Waldhoer M, Mailliard WS, Armstrong R, Bonci A, Whistler JL. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(32):11521-6. PubMed [journal]PMID: 16049099 PMCID: PMC1183554
- A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(25):9050-5. PubMed [journal]PMID: 15932946 PMCID: PMC1157030
- An opiate cocktail that reduces morphine tolerance and dependence. He L, Whistler JL. Current Biology : CB. 2005; 15(11):1028-33. PubMed [journal]PMID: 15936273
- Modulation of postendocytic sorting of G protein-coupled receptors. Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, Murray SR, Von Zastrow M. Science (New York, N.Y.). 2002; 297(5581):615-20. PubMed [journal]PMID: 12142540
- Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. He L, Fong J, von Zastrow M, Whistler JL. Cell. 2002; 108(2):271-82. PubMed [journal]PMID: 11832216
- Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Finn AK, Whistler JL. Neuron. 2001; 32(5):829-39. PubMed [journal]PMID: 11738029
- Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Ungless MA, Whistler JL, Malenka RC, Bonci A. Nature. 2001; 411(6837):583-7.
- Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M. Neuron. 1999; 23(4):737-46. PubMed [journal]PMID: 10482240.