The serotonin transporter (SLC6A4) is present in B‐cell clones of diverse malignant origin: probing a potential antitumor target for psychotropics

Meredith, Elizabeth J.; Holder, Michelle J.; Chamba, Anita; Challa, Anita; Drake-Lee, Adrian; Bunce, Christopher M.; Drayson, Mark T.; Pilkington, Geoffrey J.; Blakely, Randy D.; Dyer, Martin J. S.; Barnes, Nicholas M.; Gordon, John

doi:10.1096/fj.04-3477fje

Cited by 78 publications

(82 citation statements)

References 51 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Origin and karyotypic features of derived lines from patients with B cell malignancy are as detailed elsewhere (11). Stable bcl-2 and bcl-x L transfectants of L3055 cells and subclones containing empty vector are as described (46,47).…”

Section: Methodsmentioning

confidence: 99%

“…The identifying of classically considered neurotrophic constituents within the immune system opens up the component cells, and their pathologies, to modulation by drugs developed principally for CNS disturbances. An example of this is the finding that BL cells carry the serotonin transporter, which in turn acts as a conduit for serotonin-driven apoptosis, leading to the discovery that widely used antidepressants deliver analogous outcomes in a spectrum of NHL (11)(12)(13).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

Meredith

Holder

Rosén

et al. 2006

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

Self Cite

View full text Add to dashboard Cite

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (<10 M) micromolar range. The antiparkinsonian drugs L-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1-D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression; dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine's actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson's disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations.apoptosis ͉ oxidative stress ͉ Parkinson's disease ͉ Bcl-2 ͉ monoamines

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

Meredith

Holder

Rosén

et al. 2006

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…47 Similar to cells of the innate immune system, T helper (Th) cells also secrete cytokines, and one role of 5-HT in the immune response appears to be in modulating the balance of cells promoting the release of pro-inflammatory (Th1) versus anti-inflammatory (Th2) cytokines. 93 The actions of 5-HT in the adaptive immune system are not limited to Tcells, as 5-HT, together with platelet-activating factor (PAF), activates B cells 94 that both express SERT 61,95 and can cross the BBB, 96 albeit in very low numbers without damage to this barrier. It is known that activated T cells also cross the BBB, 97,98 and therefore, the finding that B cells may cross the BBB suggests that humoral, as well cellular, immune mechanisms may be important in the CNS, which has long been considered to exclude most peripheral immune cells.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

“…99 Because these GTPases are also expressed in lymphocytes and other immune cells, transport of 5-HT and a serotonylation pathway may act intracellularly to affect the secretory functions of lymphocytes. 95, 100 Schneider and co-workers have also described an intracellular action of 5-HT in reducing IL-4 production mediated by both SERT and the organic cation transporter 3 (OCT3). 101 How such mechanisms complement the actions of 5-HT on immune cells via cell-surface receptors is unclear, though the same can be said for platelets.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

A Dialogue between the Immune System and Brain, Spoken in the Language of Serotonin

Baganz

Blakely

2012

ACS Chem. Neurosci.

Self Cite

272

239

View full text Add to dashboard Cite

Neuropsychiatric disorders have long been linked to both immune system activation and alterations in serotonin (5-HT) signaling. In the CNS, the contributions of 5-HT modulate a broad range of targets, most notably, hypothalamic, limbic and cortical circuits linked to the control of mood and mood disorders. In the periphery, many are aware of the production and actions of 5-HT in the gut but are unaware that the molecule and its receptors are also present in the immune system where evidence suggests they contribute to the both innate and adaptive responses. In addition, there is clear evidence that the immune system communicates to the brain via both humoral and neuronal mechanisms, and that CNS 5-HT neurons are a direct or indirect target for these actions. Following a brief primer on the immune system, we describe our current understanding of the synthesis, release, and actions of 5-HT in modulating immune function, including the expression of 5-HT biosynthetic enzymes, receptors, and transporters that are typically studied with respect to the roles in the CNS. We then orient our presentation to recent findings that pro-inflammatory cytokines can modulate CNS 5-HT signaling, leading to a conceptualization that among the many roles of 5-HT in the body is an integrated physiological and behavioral response to inflammatory events and pathogens. From this perspective, altered 5-HT/immune conversations are likely to contribute to risk for neurobehavioral disorders historically linked to compromised 5-HT function or ameliorated by 5-HT targeted medications, including depression and anxiety disorders, obsessive-compulsive disorder (OCD), and autism. Our review raises the question as to whether genetic variation impacting 5-HT signaling genes may contribute to maladaptive behavior as much through perturbed immune system modulation as through altered brain mechanisms. Conversely, targeting the immune system for therapeutic development may provide an important opportunity to treat mental illness.

show abstract

“…29,22 Additionally, characterizing SERT function in PBCs may lead to better understanding of the role of serotonin in immune cell function, 30,31 blood pressure regulation, 32 and lymphocyte malignancies. 33,34 The gene that is responsible for SERT expression in the brain has been shown to code for SERT in peripheral blood cells. [35][36][37]20 Platelets are small 2−3 μM anucleate cell fragments derived from megakaryocytes that are primarily responsible for hemostasis and blood clotting.…”

mentioning

confidence: 99%

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

Beikmann

Tomlinson²,

Rosenthal³

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

The serotonin transporter (SLC6A4) is present in B‐cell clones of diverse malignant origin: probing a potential antitumor target for psychotropics

Cited by 78 publications

References 51 publications

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

A Dialogue between the Immune System and Brain, Spoken in the Language of Serotonin

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

Contact Info

Product

Resources

About