Estradiol reduced 5-HT reuptake by downregulating the gene expression of Plasma Membrane Monoamine Transporter (PMAT, Slc29a4) through estrogen receptor β and the MAPK/ERK signaling pathway

Gu, Yong; Zhang, Nanxin; Zhu, Shujie; Lu, Shuanghui; Jiang, Huidi; Zhou, Hui

doi:10.1016/j.ejphar.2022.174939

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…In three of the four studies, evidence supports sex‐specific influences of constitutive PMAT deficiency upon behaviour, 41,42,45 an observation also found with cardiovascular measures 58 . A recent report indicates that PMAT function may be reduced through an estradiol‐mediated signalling mechanism 59 . This might help explain why HT females exhibited more prominent PMAT genotype effects in psychostimulant‐induced locomotor sensitization paradigms, 42 but it remains unclear why some behavioural differences are observed in female PMAT KOs but not male PMAT KOs, or vice versa, given there are no functional PMAT to down‐regulate in these mice.…”

Section: Pmat (Slc29a4)mentioning

confidence: 65%

“…58 A recent report indicates that PMAT function may be reduced through an estradiolmediated signalling mechanism. 59 This might help explain why HT females exhibited more prominent PMAT genotype effects in psychostimulant-induced locomotor sensitization paradigms, 42 but it remains unclear why some behavioural differences are observed in female PMAT KOs but not male PMAT KOs, or vice versa, given there are no functional PMAT to down-regulate in these mice. Future studies into sex-specific effects in PMAT HT mice will advance understanding of estradiol's influences on this transporter, and as with studies in OCT3-deficient mice, use of self-administration paradigms could provide helpful information regarding PMAT's influence in responses to reinforcing stimuli.…”

Section: Pharmacological Findingsmentioning

confidence: 99%

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Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters

Weber

Beaver

Gilman

2022

Basic Clin Pharma Tox

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Burgeoning literature demonstrates that monoamine transporters with high transport capacity but lower substrate affinity (i.e., uptake 2) contribute meaningfully to regulation of monoamine neurotransmitter signalling. However, studying behavioural influences of uptake 2 is hindered by an absence of selective inhibitors largely free of off‐target, confounding effects. This contrasts with study of monoamine transporters with low transport capacity but high substrate affinity (i.e., uptake 1), for which there are many reasonably selective inhibitors. To circumvent this dearth of pharmacological tools for studying uptake 2, researchers have instead employed mice with constitutive genetic deficiency in three separate transporters. By studying baseline behavioural shifts, plus behavioural responses to environmental and pharmacological manipulations—the latter primarily targeting uptake 1—investigators have been creatively characterizing the behavioural, and often sex‐specific, influences of uptake 2. This non‐systematic mini review summarizes current uptake 2 behaviour literature, highlighting emphases on stress responsivity in organic cation transporter 2 (OCT2) work, psychostimulant responsivity in OCT3 and plasma membrane monoamine transporter (PMAT) investigations, and antidepressant responsivity in all three. Collectively, this small but growing body of work reiterates the necessity for development of selective uptake 2‐inhibiting drugs, with reviewed studies suggesting that these might advance personalized treatment approaches.

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Section: Pmat (Slc29a4)mentioning

confidence: 65%

Section: Pharmacological Findingsmentioning

confidence: 99%

Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters

Weber

Beaver

Gilman

2022

Basic Clin Pharma Tox

View full text Add to dashboard Cite

show abstract

“…Moreover, these behavioral changes in fear expression and retention were selective to males, suggesting a sex hormone component [57][58][59]. Indeed, recent studies are beginning to parse apart the molecular underpinnings of PMAT's sex-specific functions [60,61]. Until further experiments can be performed, of course, this interpretation of plasticity remains speculative.…”

Section: Discussionmentioning

confidence: 99%

Heterotypic stressors unmask behavioral influences of PMAT deficiency in mice

Weber,

Nicodemus,

Hite

et al. 2023

Preprint

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Select life stressors having enduring physiological and behavioral consequences, in part by eliciting dramatic signaling shifts in monoamine neurotransmitters. High monoamine levels can overwhelm selective transporters like the serotonin transporter. This is when polyspecific transporters like plasma membrane monoamine transporter (PMAT, Slc29a4) are hypothesized to contribute most to monoaminergic signaling regulation. Here, we employed two distinct counterbalanced stressors - fear conditioning, and swim stress - to systematically determine how reductions in PMAT function affect heterotypic stressor responsivity. We hypothesized male heterozygotes would exhibit augmented stressor responses relative to female heterozygotes. Decreased PMAT function enhanced context fear expression, an effect unexpectedly obscured by a sham stress condition. Impairments in cued fear extinction retention and enhanced context fear expression in males were conversely unmasked by sham swim condition. Abrogated corticosterone levels in male heterozygotes that underwent swim stress after context fear conditioning did not map on to any measured behaviors. In sum, male heterozygous fear behaviors proved malleable in response to preceding stressor or sham stress exposure. Combined, these data indicate reduced male PMAT function elicits a form of stress-responsive plasticity. Future studies should assess how PMAT is differentially affected in the sexes, and identify downstream consequences of the stress-shifted corticosterone dynamics.

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“…Like astrocytes, estradiol binds to ERα of microglia and inhibits transcription factor NF-γB through activation of PI3K ( 100 ). On the other hand, estradiol down-regulates the gene expression of plasma membrane monoamine transporters (PMAT, Slc29a4) through ERβ and MAPK/ERK signaling pathways, thereby reducing the reuptake of 5-HT ( 101 ). Estradiol can also increase GABA levels in hippocampus and frontal cortex through ERβ and/or GPR30, and up-regulate GABA-related genes in amygdala and hippocampus ( 102 ).…”

Section: Prevalent Mechanisms Of Perimenopausal Depressionmentioning

confidence: 99%

Neuroendocrine pathogenesis of perimenopausal depression

Qian

et al. 2023

Front. Psychiatry

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With the development of social economics and the increase of working pressure, more and more women are suffering from long-term serious stress and showing symptoms of perimenopausal depression (PMD). The incidence rate of PMD is increasing, and the physical and mental health are seriously affected. However, due to the lack of accurate knowledge of pathophysiology, its diagnosis and treatment cannot be accurately executed. By consulting the relevant literature in recent years, this paper elaborates the neuroendocrine mechanism of perimenopausal depression from the aspects of epigenetic changes, monoamine neurotransmitter and receptor hypothesis, glial cell-induced neuroinflammation, estrogen receptor, interaction between HPA axis and HPG axis, and micro-organism-brain gut axis. The purpose is to probe into new ways of treatment of PMD by providing new knowledge about the neuroendocrine mechanism and treatment of PMD.

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Estradiol reduced 5-HT reuptake by downregulating the gene expression of Plasma Membrane Monoamine Transporter (PMAT, Slc29a4) through estrogen receptor β and the MAPK/ERK signaling pathway

Cited by 11 publications

References 35 publications

Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters

Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters

Heterotypic stressors unmask behavioral influences of PMAT deficiency in mice

Neuroendocrine pathogenesis of perimenopausal depression

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