Mechanisms of Biogenic Amine Neurotransmitter Transporters

Neurotransmitter Transporters ◽

10.1385/1-59259-158-2:025 ◽

2003 ◽

pp. 025-052 ◽

Cited By ~ 24

Author(s):

Gary Rudnick

Keyword(s):

Biogenic Amine ◽

Neurotransmitter Transporters

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Structure-Function Relationships for Biogenic Amine Neurotransmitter Transporters

Neurotransmitter Transporters ◽

10.1385/1-59259-158-2:053 ◽

2003 ◽

pp. 053-109 ◽

Cited By ~ 15

Author(s):

Nian-Hang Chen ◽

Maarten E. A. Reith

Keyword(s):

Structure Function ◽

Biogenic Amine ◽

Neurotransmitter Transporters

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Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters

Nature Communications ◽

10.1038/s41467-021-22385-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shabareesh Pidathala ◽

Aditya Kumar Mallela ◽

Deepthi Joseph ◽

Aravind Penmatsa

Keyword(s):

Chronic Pain ◽

Drosophila Melanogaster ◽

Binding Site ◽

Biogenic Amine ◽

Norepinephrine Transporter ◽

Structural Basis ◽

Pain Sensation ◽

X Ray ◽

Neurotransmitter Transporters ◽

Specific Inhibitors

AbstractNorepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters.

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