Clustered Kv2.1 decreases dopamine transporter activity and internalization
| Autor: | Joseph J. Lebowitz, Cheyenne Hurst, Min Lin, Keeley Divita, Phillip Mackie, Habibeh Khoshbouei, Dimitri N. Koutzoumis, Anthony Collins, Jose A. Pino, Gonzalo E. Torres |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male media_common.quotation_subject Dopamine Biochemistry Reuptake Rats Sprague-Dawley 03 medical and health sciences Mice Shab Potassium Channels Neurobiology Mesencephalon medicine Animals Internalization Molecular Biology media_common Dopamine transporter Neurons Dopamine Plasma Membrane Transport Proteins 030102 biochemistry & molecular biology biology Chemistry Dopaminergic Transporter Cell Biology Endocytosis Cell biology Rats Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure biology.protein Female Neuron Neurotransmitter transport medicine.drug |
| Popis: | The dopamine transporter (DAT) regulates dopamine neurotransmission via reuptake of dopamine released into the extracellular space. Interactions with partner proteins alter DAT function and thereby dynamically shape dopaminergic tone important for normal brain function. However, the extent and nature of these interactions are incompletely understood. Here, we describe a novel physical and functional interaction between DAT and the voltage-gated K(+) channel Kv2.1 (potassium voltage-gated channel subfamily B member 1 or KCNB1). To examine the functional consequences of this interaction, we employed a combination of immunohistochemistry, immunofluorescence live-cell microscopy, co-immunoprecipitation, and electrophysiological approaches. Consistent with previous reports, we found Kv2.1 is trafficked to membrane-bound clusters observed both in vivo and in vitro in rodent dopamine neurons. Our data provide evidence that clustered Kv2.1 channels decrease DAT's lateral mobility and inhibit its internalization, while also decreasing canonical transporter activity by altering DAT's conformational equilibrium. These results suggest that Kv2.1 clusters exert a spatially discrete homeostatic braking mechanism on DAT by inducing a relative increase in inward-facing transporters. Given recent reports of Kv2.1 dysregulation in neurological disorders, it is possible that alterations in the functional interaction between DAT and Kv2.1 affect dopamine neuron activity. |
| Databáze: | OpenAIRE |
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