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Neuroscience Graduate Program at UCSF

Faculty - Jennifer Whistler, Ph.D.

GPCR Trafficking and the Regulation of Responsiveness to Drugs of Abuse


Research Description

My laboratory studies the trafficking of GPCRs important in addiction, pain and neuropsychiatric disease.  We have active programs studying opioid, dopamine, and cannabinoid receptors and several collaborations and pilot projects with other GPCRs. Our most advanced project has focused on the mu opioid receptor (MOR), one of three members of the opioid receptor family. Like most GCPRs, the MOR undergoes a cascade of regulatory events following its activation by endogenous peptide ligands, such as enkephalin and endorphin. These include phosphorylation by GPCR kinases (GRKs), recruitment of arrestin, and endocytosis.  Following its endocytosis, the MOR is then dephosphorylated and recycled to the plasma membrane where it is available for the next round of signal transduction (Whistler et al., Science 2002).  Several opioid agonist drugs behave like endogenous peptide ligand with regards to receptor trafficking, including methadone, etorphine and, at high concentrations, fentanyl. However, the prototypical, and clinically most common, opioid agonist drugs, including morphine and oxycodone (and heroin), fail to promote endocytosis of the MOR. My laboratory has hypothesized that the failure of morphine to promote endocytosis of the MOR contributes to the high liability of this drug to promote the side of effects of analgesic tolerance and withdrawal symptoms indicative of physical dependence.  This hypothesis is supported by our observations that, at equi-analgesic doses, agonists such as methadone and enkephalin have a reduced liability, compared to morphine, to promote tolerance and dependence in rodent models. However, each time a different drug is used in these paradigms, not only is endocytosis of the receptor altered, but also multiple other pharmacological properties including ligand affinity, potency, efficacy and bioavailability. Thus, it has been difficult, using pharmacology alone, to examine the precise role of receptor endocytosis in tolerance and dependence.

To directly assess the role of MOR trafficking in the development of tolerance and dependence to morphine, we therefore generated mutant receptors that are phosphorylated, recruit arrestin and are endocytosed in response to morphine.  One of these receptors, RMOR, is endocytosed and recycled with morphine. In cell-based models we demonstrated that the RMOR receptors show opioid pharmacology undistinguishable from wild-type MORs (affinity, efficacy, potency) and reduced cAMP superactivation in response to chronic morphine, a cellular hallmark of tolerance and dependence.  We also have developed a MOR, AMOR, that is not endocytosed even upon activation by endogenous peptide or methadone, due to mutation of the GRK phosphorylation sites. In our cell-based work, we demonstrated that cAMP superactivation was enhanced in response to methadone in cells expressing the AMOR receptors (Finn and Whistler, Neuron 2001).  This strong cell-based data, demonstrating that enhancing endocytosis decreases, while preventing endocytosis increases, a cellular hallmark of tolerance and dependence, inspired us to generate a knock-in mouse that expresses the RMOR receptor.  Pharmacological and histological analysis showed that receptor expression, number, affinity and signaling of the MOR and RMOR receptors were indistinguishable. In addition, analgesia to morphine was enhanced in RMOR mice compared to their wild-type littermates.  Thus, desensitization and endocytosis of the receptor does not decrease the efficacy of morphine, presumably because the receptor is rapidly recycled and thus resensitized following endocytosis. Analgesia in the RMOR mice is selectively enhanced in response to morphine, as methadone analgesia is indistinguishable between WT and RMOR mice. Together these data imply that it is specifically the endocytosis of the receptor in response to morphine that is enhancing analgesia. Importantly, mice expressing the RMOR receptor also develop substantially reduced tolerance and dependence to morphine despite the fact that it is a better analgesic in these mice (Kim et al, Current Biology, 2008).  Ongoing experiments are examining whether biochemical, pharmacological and electrophysiological hallmarks of tolerance and dependence are altered in the RMOR mice compared to their MOR littermates. Ongoing experiments are also designed to model addiction in the MOR and RMOR mice to determine whether endocytosis contributes not only to the adaptive changes responsible for analgesic tolerance and dependence, but also to the changes responsible for drug reinforcement, reward, craving and relapse in a mouse model of operant self-administration. In short, these mice will provide an outstanding model to dissect the specific changes in gene expression and neuronal plasticity that are responsible for tolerance and dependence.

Taken together our existing data imply that opioid drugs with the pharmacological properties of morphine, but the ability to promote endocytosis of the MOR would be outstanding analgesics with a reduced propensity for promoting tolerance and dependence.  We have developed one such opioid that takes advantage of the observation that the MOR appears to form dimers/oligomers. A cocktail consisting of an analgesic dose of morphine plus a small, non analgesic dose of methadone (or enkephalin) promotes endocytosis of the MOR, presumably because a single methadone-occupied protomer of the MOR is sufficient to promote endocytosis of an oligomeric complex containing both methadone and morphine-occupied receptors (He et al, Cell 2002, He et al Current Biology, 2005). Rats receiving morphine alone develop tolerance and dependence within 5 days.  However, rats receiving a cocktail consisting of the same dose of morphine spiked with a small dose of methadone, that promotes MOR endocytosis, do not develop tolerance and dependence.  Lower doses of methadone, that do not promote morphine-induced endocytosis, do not prevent tolerance and dependence (He et al, Current Biology 2005). The long-term goal is to test the morphine-methadone cocktail in human pain trials for analgesic tolerance.

The studies with the opioid cocktail, led us to believe that opioid receptor dimers do, in fact, exist. Indeed, we have observed that opioid receptors exist as both homomeric and heterodimeric receptor complexes. We have identified an opioid receptor ligand that is an antagonist at homomeric delta opioid receptors (DORs) but a potent agonist at heterodimers of the DOR and kappa opioid receptor (KOR) (Waldhoer et. al,  PNAS 2005).  We found this ligand is a tissue-selective analgesic showing good antinociceptive potency spinally but not centrally. This was the first demonstration of functional relevance of an opioid receptor heterodimer. These data suggest that opioid receptor heterodimers do indeed exist in vivo and could represent novel and pharmacologically distinct targets, possibly with tissue-selective expression.

Opioid receptors are not only important targets for analgesia, but also one of the few targets currently available for the treatment of alcoholism.  Naltrexone, a non-selective opioid receptor antagonist, has shown limited efficacy for the treatment of alcoholism.  This may be due, in part, to the non-selective nature of this drug.  Current efforts in the laboratory are focused on identifying whether particular opioid receptor subtypes or heterodimers could be more effective targets for the treatment of alcoholism. We are also examining whether the composition or distribution of opioid receptor heterodimers or subtypes is altered in several disease models, including chronic pain, morphine tolerance, drug sensitization, and chronic alcohol consumption. To facilitate these studies, we have generated mice with a disruption of each opioid receptor gene. To facilitate our efforts to map the brain areas and circuits responsible for opioid receptor related behaviors we have also generate transgenic mice with a conditional “floxed” allele of each opioid receptor gene.  

Following their endocytosis, GPCRs can be either recycled to the plasma membrane, which serves to “resensitize” cells to the next agonist exposure, or they can be targeted for degradation, which leads to downregulation of receptor function. We have found that the MOR is a “recycling” receptor  while the DOR is targeted for degradation.  This degradation appears to be modulated through interaction with GPCR-associated sorting protein (GASP) (Whistler et. al, Science 2002). We have found that GASP interacts with members of several other GPCR families including the cannabinoid CB1 receptor (Martini et al, FASEB J. 2007), the D2 dopamine receptor (Bartlett et al, PNAS 2005), and the Bradykinin B1 receptor (Enquist et. al, Mol. Pharm. 2006) as well as several mutant GPCRs whose trafficking has switched from recycling to degradation (Thompson et. al, JBC 2007).
           
Importantly, we found that interaction of the CB1 receptor with GASP promotes downregulation of the receptor (Martini et. al, FASEB J. 2007).  Disrupting the interaction between GASP and the CB1 prevents agonist-induced receptor downregulation in vivo and the development of analgesic tolerance to spinal cannabinoids (Tappe-Theodore et. al, J. Neurosci. 2007).

In the dopamine receptor family, we have found that D2 but not D1 receptors bind GASP and are targeted for post-endocytic degradation (Bartlett et. al, PNAS 2005). This observation has significant implications towards our understanding of dopaminergic signaling, which is altered in several neuropsychiatric diseases including Parkinson’s disease, schizophrenia, attention deficit hyperactivity disorder and depression.  Both D1 and D2 dopamine receptors respond to the same agonist ligand, dopamine.  However, they are coupled to G proteins with profoundly different signaling outcomes.  Hence, if D1 and D2 receptors have different post-endocytic fates following activation by dopamine, a second dopamine exposure of a cell or a circuit that expresses both receptor types would be expected to have an altered signaling profile, with a D1 response predominating.  Current studies are aimed and elucidating the role of GASP-mediated GPCR degradation in several disease models using mice with a disruption of the GASP gene.

In summary, we have developed a unique set of tools, including cell lines and transgenic animals, that allow us to evaluate the role of GPCR trafficking in adaptations to chronic treatment with drug, and in animal models of neuropsychiatric disease. My laboratory integrates multiple approaches, including cell biology, pharmacology, electrophysiology and in vivo models of behavior to address the role of receptor trafficking in addiction and other neuropsychiatric diseases. Thus, for each project and receptor class, we have translated our in vitro and cell-based observations to preclinical animals models. We are also actively pursuing clinical partners for development of novel opioid receptor ligands or ligand cocktails for treatment of chronic pain without the development of opioid tolerance.

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Current Projects

See Research Description

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Lab Members

Li He M.D.
Senior Research Scientist
lih@gallo.ucsf.edu

Richard M. van Rijn Ph.D.
Assistant Research Scientist
rvanrijn@gallo.ucsf.edu

Anuradha Madhavan Ph.D.
Postdoctoral Fellow
amadhavan@gallo.ucsf.edu

Johan Enquist Ph.D.
Postdoctoral Fellow
jenquist@gallo.ucsf.edu

Laura Milan-Lobo Ph.D.
Postdoctoral Fellow
lmilanlobo@gallo.ucsf.edu

Jessica Harvey, Ph.D.
Postdoctoral Fellow
jharvey@gallo.ucsf.edu

Pia Tschische
Postdoctoral Fellow
ptschische@gallo.ucsf.edu

Madeline Ferwerda
Staff Research Associate
Lab/Colony Manager
madelinef@gallo.ucsf.edu

Derek Hok
Staff Research Associate
dhok@gallo.ucsf.edu

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Selected Publications

D. Thompson, J.L. Whistler. 2011. Dopamine D3 receptors are downregulated following heterologous endocytosis by a specific interaction with GPCR-associated sorting protein-1. J Biol Chem. Jan 14;286(2):1598-608.

D. Thompson, J.L. Whistler. 2011. Trafficking properties of the D5 dopamine receptor. Traffic, May;12(5):644-56.

A.C. Berger, J.L. Whistler. 2011. Morphine-Induced Mu Opioid Receptor Trafficking Enhances Reward Yet Prevents Compulsive Drug Use. EMBO Molecular Medicine, Jul;3(7):385-97.

L. He, J.L. Whistler. 2011. Chronic ethanol consumption produces opioid antinociceptive tolerance through inhibition of mu opioid receptor endocytosis. PLoS One, 6(5):e19372.

L. Milan-Lobo, J.L. Whistler. 2011. Heteromerization of the mu and delta opioid receptor alters mu receptor trafficking. J Pharmacol Exp Ther. Jun;337(3):868-75.

R. van Rijn, L. He, D.I. Brissett, J.L. Whistler. 2011. Emergence of functional spinal delta opioid receptors after chronic ethanol exposure. Biological Psychiatry. Aug. 31.

D.I. Brissett, J.L. Whistler, R. van Rijn. 2011. Contribution of mu and delta opioid receptors to the pharmacological profile of kappa opioid receptor subtypes.  European Journal of Pain.  In press.

R. van Rijn, D.I. Brissett, J.L. Whistler. 2011. Distinctive modulation of ethanol place preference by delta opioid receptor-selective agonists. Drug and Alcohol Dependence. In press.

N. Tschammer,J, Elsner,  A. Götz,  K. Ehrlich, S. Schuster, M. Ruberg,  J. Kühhorn,  D. Thompson,  J. Whistler, H. Hübner,  P. Gmeiner. 2011. Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D(3) Receptor Binding, Functional Selectivity and Analysis of Receptor-Ligand Interactions. J. Med. Chem. Apr 14;54(7):2477-91.

J. Enquist, J.A. Kim, S. Bartlett, M. Ferwerda and J.L. Whistler. 2011. A novel knock-in mouse reveals mechanistically distinct forms of morphine tolerance. J Pharmacol Exp Ther, Aug;338(2):633-40.

J. Kargl, N. Balenga, W. Platzer, L. Martini, J. Whistler, M. Waldhoer. 2011. The GPCR - associated sorting protein 1 regulates drug-induced downregulation of GPR55. Br. J. of Pharmacology. Jun 30.

A. Madhavan, G. Stuber, A. Bonci, J.L. Whistler. 2010. micro-Opioid receptor endocytosis prevents adaptations in ventral tegmental area GABA transmission induced during naloxone-precipitated morphine withdrawal. J. Neuroscience. Mar 3;30(9):3276-86.

R.M. van Rijn, J.L. Whistler, Waldhoer M. 2010. Opioid receptor heteromer specific trafficking and pharmacology. Curr Opin Pharmacol. Feb;10(1):73-9.

L. Martini, D. Thompson, V. Kharzia, J.L. Whistler. 2010. Differential regulation of behavioral tolerance to WIN55,212-2 byGASP1. Neuropsychopharmacology. Jul 1;80(1):86-94. Featured with the cover.

A.C. Berger, J.L. Whistler. 2010. How to design an opioid drug that causes reduced tolerance and dependence.  Annals of Neurology. May;67(5):559-69.

D. Thompson, L. Martini, J.L. Whistler. 2010 Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine. PLoS One. 2010 Jun 9;5(6):e11038.

R.M. van Rijn, DI Brissett, J.L. Whistler. 2010. Dual efficacy of delta opioid receptor selective ligands for ethanol drinking and anxiety. J Pharmacol Exp Ther. Oct;335(1):133-9.

A. Madhavan, A. Bonci, J.L. Whistler. 2010. Opioid-induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area. J. Neuroscience. Oct 20;30(42):14029-35.

P. Tschische, E. Moser, D. Thompson, H.F. Vischer, G.P. Parzmair, V. Pommer, W. Platzer, T.Schwarzbraun, H. Schaider, M.J. Smit, L. Martini, J.L. Whistler, M. Waldhoer. 2010. The G protein coupled receptor associated sorting protein GASP-1 regulates the signaling and trafficking of the viral chemokine receptor US28. Traffic. May;11(5):660-74.

C. M. Henstridge, N. A. B. Balenga, R. Schröder, J. K. Kargl, W. Platzer, L. Martini, S. Arthur, J. Penman, J.L. Whistler, E. Kostenis, M. Waldhoer and A. J. Irving. 2010. GPR55 ligands promote receptor coupling to multiple signalling pathways. British Journal of Pharmacology. Jun;160(3):604-14.

M.M. Bonde, R. Yao, J-N. Ma, S. Madabushi, S. Haunsø, E.S. Burstein; J.L. Whistler, S.P. Sheikh, O. Lichtarge, J.L. Hansen. 2010. An angiotensin II type 1 receptor activation switch patch revealed through evolutionary trace analysis. Biochemical Pharmacology. Jul 1;80(1):86-94.

E. Moser, J. Kargl, J. L. Whistler, M. Waldhoer, P. Tschische. 2010. G Protein-Coupled Receptor-Associated Sorting Protein 1 Regulates the Postendocytic Sorting of Seven-Transmembrane-Spanning G Protein-Coupled Receptors. Pharmacology 2010;86:22-29

L. He , J.A. Kim, J.L. Whistler. 2009. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant {micro}-opioid receptor. FASEB Dec;23(12):4327-34.

J.L. Whistler. 2009. Ligand selective receptor desensitization and endocytosis. In Functional Selectivity of G Protein-Coupled Receptors: New opportunities for drug discovery. Humana Press.

R. Schröder , N. Merten, J.M. Mathiesen, L. Martini, A. Kruljac-Letunic, F. Krop, A. Blaukat, Y. Fang, E. Tran, T. Ulven, C. Drewke, J. Whistler, L. Pardo, J. Gomeza, Kostenis E. 2009. The C-terminal tail of CRTH2 is a key molecular determinant that constrains Galphai and downstream signaling cascade activation. J Biol Chem. 2009 Jan 9;284(2):1324-36.

L. He, J. Kim, C. Ou, W. McFadden, R. van Rijn and J.L. Whistler 2009. Methadone antinociception is dependent on peripheral opioid receptors. J Pain. Apr;10(4):369-79.

M.J. Wallace, P.M. Newton, T. McMahon, J. Connolly, A. Huibers, J. Whistler, R.O. Messing. 2009. PKCepsilon regulates behavioral sensitivity, binding and tolerance to the CB1 receptor agonist WIN55,212-2. Neuropsychopharmacology. Jun;34(7):1733-42.

A. Ravindranathan, G. Joslyn, M. Robertson, M.A. Schuckit, J.L. Whistler, R.L. White. 2009. Functional characterization of human variants of the mu-opioid receptor gene. Proc Natl Acad Sci U S A. Jun 30;106(26):10811-6

R.M. van Rijn, J.L. Whistler. 2009. The delta(1) Opioid Receptor Is a Heterodimer That Opposes the       Actions of the delta(2) Receptor on Alcohol Intake. Biological Psychiatry. Oct 15;66(8):777-84

J. Kim, S. Bartlett, L. He, C. Nielsen, A. Chang, V. Kharazia, C.J. Ou, M. Waldhoer, S. Taylor, M. Ferwerda, D. Cado,  and J.L. Whistler. 2008. Morphine-induced endocytosis of the mu opioid receptor in a novel knock in mouse reduces tolerance and dependence. Current Biology Jan 17;18(2):129-135.

Y. Xia, L. He, J.L. Whistler Hjelmstad G.O. 2008. Acute amphetamine exposure selectively desensitizes kappa opioid receptors in the nucleus accumbens. Neuropsychopharmacology. 2008 Mar;33(4):892-900.

R.M. van Rijn RM, J.L. Whistler. 2008. The only way is up: preventing opioid tolerance by promoting cell surface expression of MOR-DOR heterodimers? Mol Interv. Dec;8(6):277-80.

A.W. Lasek, P.H. Janak, L. He, J.L. Whistler, Heberlein U. 2007. Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice. Genes Brain Behav. Nov;6(8):728-35.

 L. He, J.L. Whistler2007. The Biochemical Analysis of Methadone Modulation on Morphine-Induced Tolerance and Dependence in the Rat Brain. Pharmacology. 2007 Mar 15;79(4):193-202

J. Enquist, C. Skroder C, J.L. Whistler, L.M. Leeb-Lundberg. 2007. Kinins promote B2 receptor endocytosis and delay constitutive B1 receptor endocytosis. Mol Pharmacol. Feb;71(2):494-507. Epub 2006 Nov 16.

D. Thompson, M. Pusch and J.L. Whistler. 2007.  Changes in G protein coupled receptor associated protein, GASP regulate sorting of G protein coupled receptors. Journal of Biological Chemistry, 2007, 282(40):29178-85.

L. Martini, J.L. Whistler. 2007. The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence. Curr Opin Neurobiol. 2007 Oct;17(5):556-64.

Tappe-Theodor, N. Agarwal, I Katona, T. Rubino, L. Martini, J. Swiercz, K. Mackie, H. Monyer, D. Parolaro, J. Whistler, T. Kuner, R. Kuner.  2007. A molecular basis of analgesic tolerance to cannabinoids. J Neurosci.  Apr 11;27(15):4165-77.

Martini L, Waldhoer M, Pusch M, Kharazia V, Fong J, Lee JH, Freissmuth C, Whistler JL2007. Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. FASEB J. Mar;21(3):802-11.

L. He, J.L. Whistler. 2005. An opiate cocktail that reduces morphine tolerance and dependence. Curr Biol. 15(11):1028-33.

E. Kostenis, L. Martini, J. Ellis ,M Waldhoer , A Heydorn, MM Rosenkilde, PK Norregaard, R Jorgensen, J.L. Whistler, G. A. Milligan. 2005. A highly conserved glycine within linker I and the extreme C terminus of G protein alpha subunits interact cooperatively in switching G protein-coupled receptor-to-effector specificity. J Pharmacol Exp Ther. 313(1):78-87.

S.E. Bartlett, J. Enquist , F.W. Hopf, J.H. Lee, F. Gladher , V. Kharazia, M. Waldhoer, W.S. Mailliard, R. Armstrong, A. Bonci A, J.L. Whistler. 2005. Dopamine responsiveness is regulated by targeted sorting of D2 receptors. Proc Natl Acad Sci U S A. 102(32):11521-6

M. Waldhoer, J. Fong, R.M. Jones, M.M. Lunzer, S.K. Sharma, E. Kostenis, P.S. Portoghese, J.L. Whistler J.L. 2005. A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci U S A. Jun 21;102(25):9050-5.

S.E. Bartlett and J.L. Whistler. 2004. Oligomerization and Trafficking (book chapter) G-Protein Coupled receptors: Signaling, Dimerization, and Neuropharmacology Contemporary Clinical Neuroscience.

M. Waldhoer, S.E. Bartlett and J.L. Whistler. 2004. Opioid Receptors. Ann. Rev. Biochem. 73: 953-990.

A. Heydorn, B.P. Søndergaard, B. Ersbøll, B. Holst, F.C. Nielsen, C. R. Haft, J.L. Whistler, T.W. Schwartz. 2004. A library of 7TM receptor C-terminal tails. Interactions with the proposed post-endocytic sorting proteins ERM-binding phosphoprotein 50 (EBP50), N-ethylmaleimide-sensitive factor (NSF), sorting nexin 1 (SNX1), and G protein-coupled receptor-associated sorting protein (GASP). J Biol Chem. 279(52):54291-303

M. Waldhoer, P. Casarosa, M.M. Rosenkilde, M.J. Smit, R. Leurs, J.L. Whistler, Schwartz, T.W. 2003. The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis. J Biol Chem. 278(21): 19473-19482.

L. He J. Fong M. von Zastrow and J.L. Whistler. 2002. Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell, vol.108 271-282 Also featured with a minireview.

V. A. Alvarez, S. Arttamangkul, V. Dang, A. Salem, J.L. Whistler, M. von Zastrow, D. Grandy and J. T. Williams.  2002. µ-Opioid receptors: activation of potassium conductance, desensitization and internalization. J. Neuroscience 22, 5769-5776

J.L. Whistler, J. Enquist, A. Marley, J. Fong, F. Gladher, P. Tsuruda, S. Murray, and M. von Zastrow. 2002. Modulation of postendocytic sorting of G protein-coupled receptors. Science 297, 615-620. Also featured with a perspective Science 297, 529.

J.L. Whistler, B.O. Gerber, E. Meng, T. Baranski, M. von Zastrow and H.R. Bourne. 2002. Constitutive activation and endocytosis of the complement factor 5a receptor: evidence for multiple activated conformations of a G protein-coupled receptor. Traffic, 3(12): 866-877. Also featured with the cover.

S.E. Bartlett and J.L. Whistler. 2002. The near death experience of delta opioid receptors leads to new drug targets. Molecular Interventions, 2(3) 12-14

J.L. Whistler, P. Tsao, and M. von Zastrow. 2001. A phosphorylation-regulated brake mechanism controls the initial endocytosis of opioid receptors but is not required for post-endocytic sorting to lysosomes. JBC, 276 34331-34338.

M. Ungless, J.L. Whistler, R. Malenka, A. Bonci. 2001. Single cocaine exposure in vivo induces long term potentiation in midbrain dopamine cells. Nature, 411 583-587.

A.K. Finn and J.L. Whistler. 2001. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal.  Neuron, 32 (5) 829-839 Also featured with the cover and a minireview

J.L. Whistler, E. Beattie and M. von Zastrow. 2000. Tales from the crypt: Evidence for heptahelical receptor signaling in the endocytic pathway. Science's STKE, 29 August.

J.L. Whistler and M. von Zastrow.  1999. Dissociation of functional roles of dynamin in receptor-mediated endocytosis and mitogenic signal transduction. JBC, 274 (35) 24575-24578

J.L. Whistler, H-h. Chuang, P. Chu, L.Y. Jan and M. von Zastrow. 1999. Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron, 23  737-746 Also featured with the cover and a minireview.J.L. Whistler and M. von Zastrow.  1998. Morphine-activated opioid receptors elude desensitization by beta-arrestin. PNAS, 95 9914-9919

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Jennifer Whistler, Ph.D.



Email

jennifer.whistler@ucsf.edu

Phone

415-502-7236

Office Address

UCSF, Mission Bay, Box
675 Nelson Rising Lane, room 211C
San Francisco, CA 94158

Other Websites

Gallo Website

The Wheeler Center for the Neurobiology of Addiction