Clustered Kv2.1 decreases dopamine transporter activity and internalization

Citations Over TimeTop 24% of 2019 papers

Abstract

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.

Related Papers

• → Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine(2003)229 cited
• → Dopamine transporter phosphorylation site threonine 53 is stimulated by amphetamines and regulates dopamine transport, efflux, and cocaine analog binding(2017)37 cited
• → A Physical Interaction between the Dopamine Transporter and DJ-1 Facilitates Increased Dopamine Reuptake(2015)19 cited
• → Radiation inactivation studies of the dopamine reuptake transporter protein.(1994)42 cited
• → Molecular model of the neural dopamine transporter(2003)33 cited