PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein

Hamilton, Peter J.; Belovich, Andrea N.; Khelashvili, George; Saunders, Christine; Erreger, Kevin; Javitch, Jonathan A.; Sitte, Harald H.; Weinstein, Harel; Matthies, Heinrich J.G.; Galli, Aurelio

doi:10.1038/nchembio.1545

Cited by 116 publications

(185 citation statements)

References 49 publications

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“…Similar findings were reported for site-directed mutagenesis of Thr 62 (Fraser et al, 2014), and by Khoshbouei et al (2003), who reported that Nterminal phosphorylation shifts DAT from a "reluctant" state to a "willing" state for d-amphetamine-induced DA efflux, without affecting inward transport. Moreover, a recent study showed that impairing the interaction of phosphatidylinositol 4,5-bisphosphate with DAT impairs amphetamine-induced DA efflux without affecting DA uptake (Hamilton et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Studies of the Biogenic Amine Transporters 15. Identification of Novel Allosteric Dopamine Transporter Ligands with Nanomolar Potency

Rothman

Ananthan

Partilla

et al. 2015

J Pharmacol Exp Ther

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Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that [N-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) fullefficacy agents with a two-site fit, and 3) partial-efficacy agents with a one-site fit-the focus of further studies. These agents partially inhibited DA, serotonin, and norepinephrine uptake, yet were much less potent at inhibiting [ release. These compounds may prove to be useful probes of biogenic amine transporter function as well as novel therapeutics.

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Section: Resultsmentioning

confidence: 99%

Studies of the Biogenic Amine Transporters 15. Identification of Novel Allosteric Dopamine Transporter Ligands with Nanomolar Potency

Rothman

Ananthan

Partilla

et al. 2015

J Pharmacol Exp Ther

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“…Hamilton et al (2014) provided the first evidence for interactions of PIP 2 with DAT via coimmunoprecipitation studies using either transfected cells or brain extracts. Consistent with findings of PIP 2 interactions with the SERT N terminus (see below), these authors found that the DAT N terminus interacts with PIP 2 , mediated by electrostatic interactions involving residues K3 and K5.…”

Section: A Phosphatidylinositol 3-kinase/akt Regulation Of Dopamine mentioning

confidence: 99%

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Bermingham

Blakely

2016

Pharmacol Rev

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“…Consistent with this model, MD simulations of DAT 28 and SERT 31 have displayed spontaneous outward-open to inward-open transition upon destabilization and inward release of the sodium from the Na2 site. From analysis of microsecond-long MD trajectories 28 we discovered that the release of the sodium from the Na2 site (referred to hereafter as Na + /Na2) in the human DAT (hDAT) can be allosterically triggered by interactions of the N-terminus region of the transporter (residues 1-59) with various other regions of the transporter, and that some of these interactions are electrostatically driven and supported by the highly charged (− 4e at neutral pH) PI(4,5)P 2 (phosphatidylinositol 4,5-biphosphate) lipids in the membrane 28,34,35 . One important aspect of the transport cycle that has not been resolved relates to the kinetics of Na + ion dissociation from the Na2 site, which is essential for building kinetic models that could describe quantitatively the allosteric mechanisms involved in function of the NSS 36 .…”

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confidence: 99%

Markov State-Based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

Razavi

Khelashvil

Weinstein

2017

Biophysical Journal

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The dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.The dopamine transporter (DAT) is a transmembrane (TM) secondary transporter protein belonging to the Neurotransmitter:Sodium Symporter (NSS) family, which also includes the closely related serotonin (SERT) and norepinephrine (NET) transporters 1 . The NSS are responsible for clearance of released neurotransmitters (e.g. dopamine (DA), by DAT) from the synaptic cleft through their translocation back into the presynaptic nerve termini. The function of NSS transporters in neuronal signaling implicate them in the mechanisms of action of abused psychostimulants, such as cocaine and amphetamine 2,3 , and in various psychiatric and neurological disorders including drug addiction, schizophrenia, and Parkinson's disease 3 . These essential neurophysiological roles have made NSS transporters primary targets for antidepressant medications.Breakthrough crystallographic determinations of members of the NSS family includes the bacterial homolog LeuT 4,5 , and most recently the structures of Drosophila DAT (dDAT) [6][7][8] . Structures of these transporters have been determined in complex with various substrates and ligands in the primary (S1) and secondary (S2) binding sites and with sodium ions bound in sites Na1 and Na2. They have offered an essential molecular context for the investigation of the mechanism of uphill neurotransmitter reuptake transport enabled by the coupling with the transmembrane Na + gradient 1,10 . Our current understanding of functional mechanisms in NSS has been further shaped by the large body of structure-function studies of LeuT and other related bacterial transporters, carried out both experimentally 11-17 and computationally [11][12][13][14]16,[18][19][20][21][22][23] , and more recently by findings from molecular dynamics (MD) simulat...

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PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein

Cited by 116 publications

References 49 publications

Studies of the Biogenic Amine Transporters 15. Identification of Novel Allosteric Dopamine Transporter Ligands with Nanomolar Potency

Studies of the Biogenic Amine Transporters 15. Identification of Novel Allosteric Dopamine Transporter Ligands with Nanomolar Potency

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Markov State-Based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

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