Developing novel treatments for mood disorders: accelerating discovery

Tamminga, Carol A.; Nemeroff, Charles B.; Blakely, Randy D.; Brady, Linda S.; Carter, Cameron S.; Davis, Kenneth L.; Dingledine, Raymond; Gorman, Jack M.; Grigoriadis, Dimitri E.; Henderson, David C.; Innis, Robert B.; Killen, Jack; Laughren, Thomas; McDonald, William M.; Murphy, Greer M.; Paul, Steven M.; Rudorfer, Matthew V.; Sausville, Edward A.; Schatzberg, Alan F.; Scolnick, Edward M.; Suppes, Trisha

doi:10.1016/s0006-3223(02)01470-1

Cited by 67 publications

(46 citation statements)

References 71 publications

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“…These agents are differential selective for SERT, NET, and DAT, and their clinical efficacy varies considerably across the population (10,12). Transporter-specific cellular regulation has the potential to lead to novel and selective therapeutic approaches that manipulate transporters intrinsically, rather than extrinsically.…”

Section: Discussionmentioning

confidence: 99%

“…Transporter inhibitors with differential DAT, SERT, and NET specificity are widely used to treat neuropsychiatric disorders (10,11). However, their therapeutic efficacy differs significantly among patients, consistent with the model that monoamines may differentially contribute to the pathogenesis of these disorders (10,12). Thus, regulatory mechanisms specific to DAT, SERT, or NET may provide a novel route to develop transporter-specific therapeutics.…”

mentioning

confidence: 83%

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Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant

Bellvé

Fogarty

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

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The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attentiondeficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKCsensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability. However, the molecular basis for the DAT endocytic brake is unknown, and it is unknown whether this braking mechanism is unique to DAT or common to monoamine transporters. Here, we report that the cdc42-activated, nonreceptor tyrosine kinase, Ack1, is a DAT endocytic brake that stabilizes DAT at the plasma membrane and is released in response to PKC activation. Pharmacologic and shRNA-mediated Ack1 silencing enhanced basal DAT internalization and blocked PKC-stimulated DAT internalization, but had no effects on SERT endocytosis. Both cdc42 activation and PKC stimulation converge on Ack1 to control Ack1 activity and DAT endocytic capacity, and Ack1 inactivation is required for stimulated DAT internalization downstream of PKC activation. Moreover, constitutive Ack1 activation is sufficient to rescue the gain-of-function endocytic phenotype exhibited by the ADHD DAT coding variant, R615C. These findings reveal a unique endocytic control switch that is highly specific for DAT. Moreover, the ability to rescue the DAT(R615C) coding variant suggests that manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct DAT coding variants that exhibit trafficking dysregulation.is a modulatory neurotransmitter critical for locomotion and reward (1), and dopaminergic (DAergic) dysregulation is linked to multiple neuropsychiatric disorders, including Parkinson's disease, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) (2, 3). Presynaptic recapture, facilitated by the high-affinity DA transporter (DAT), spatially and temporally restricts extracellular DA availability (4-6). Addictive psychostimulants that target DAT and its monoamine transporter homologs for 5HT (SERT) and NE (NET) are either competitive ligands, such as cocaine, or competitive substrates, such as amphetamine (7). Although these drugs interact with DAT, SERT, and NET with equimolar affinity, their binding to DAT is requisite for reward (8, 9). Transporter inhibitors with differential DAT, SERT, and NET specificity are widely used to treat neuropsychiatric disorders (10, 11). However, their therapeutic efficacy differs significantly among patients, consistent with the model that monoamines may differentially contribute to the pathogenesis of these disorders (10, 12). Thus, regulatory mechanisms specific to DAT, SERT, or NET may provide a novel route to develop transporter-specific therapeutics.DAT plasma membrane expression is req...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant

Bellvé

Fogarty

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), and propidium iodide (PI) were purchased from Life Technologies (Grand Island, NY). Serotonin (5-HT), paroxetine (PRX), imipramine (IMI), NH 4 Cl, KHCO 3 , Na 2 EDTA, DMSO, and prostaglandin E1 were purchased from Sigma-Aldrich (St Louis, MO). Clomipramine (CMI) was purchased from Sigma Aldrich/RBI (Natick, MA).…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Serotonin Uptake Is Largely Mediated by Platelets versus Lymphocytes in Peripheral Blood Cells

Beikmann

Tomlinson²,

Rosenthal³

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:The serotonin transporter (SERT), a primary target for many antidepressants, is expressed in the brain and also in peripheral blood cells. Although platelet SERT function is well accepted, lymphocyte SERT function has not been definitively characterized. Due to their small size, platelets often are found in peripheral blood mononuclear cell preparations aimed at isolating lymphocytes, monocytes, and macrophages. The presence of different cells makes it difficult to assign SERT expression and function to specific cell types. Here, we use flow cytometry and IDT307, a monoamine transporter substrate that fluoresces after uptake into cells, to investigate SERT function in lymphocyte and platelet populations independently, as well as simultaneously without prior isolation. We find that murine lymphocytes exhibit temperature-dependent IDT307 transport but uptake is independent of SERT. Lack of measurable SERT function in lymphocytes was corroborated by chronoamperometry using serotonin as a substrate. When we examined rhesus and human mixed blood cell populations, we found that platelets, and not lymphocytes, were primary contributors to SERT function. Overall, these findings indicate that lymphocyte SERT function is minimal. Moreover, flow cytometry, in conjunction with the fluorescent transporter substrate IDT307, can be widely applied to investigate SERT in platelets from populations of clinical significance.

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“…Antidepressants, the third most commonly prescribed class of medications in the US, have been shown to reduce the symptoms of major depressive disorder, but these drugs are generally better than placebo only after 6 weeks of administration and in most studies, patients on medication continue to have substantial depressive symptoms. 22 A consensus definition of remission published in 1991 has helped the field to measure remission as a target in the treatment of major depressive disorder. How often do SSRIs result in remission?…”

Section: Limitations: the Glass Half Emptymentioning

confidence: 99%

Cure therapeutics and strategic prevention: raising the bar for mental health research

2005

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Mental disorders cause more disability than any other class of medical illness in Americans between ages 15 and 44 years. The suicide rate is higher than the annual mortality from homicide, AIDS, and most forms of cancer. In contrast to nearly all communicable and most non-communicable diseases, there is little evidence that the morbidity and mortality from mental disorders have changed in the past several decades. Mental health advocates, including psychiatric researchers, have pointed to stigma as one of the reasons for the lack of progress with mental illnesses relative to other medical illnesses. This review considers how the expectations and goals of the research community have contributed to this relative lack of progress. In contrast to researchers in cancer and heart disease who have sought cures and preventions, biological psychiatrists in both academia and industry have set their sights on incremental and marketable advances, such as drugs with fewer adverse effects. This essay argues for approaches that can lead to cures and strategies for prevention of schizophrenia and mood disorders.

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Developing novel treatments for mood disorders: accelerating discovery

Cited by 67 publications

References 71 publications

Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant

Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant

Serotonin Uptake Is Largely Mediated by Platelets versus Lymphocytes in Peripheral Blood Cells

Cure therapeutics and strategic prevention: raising the bar for mental health research

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