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Full-Text Articles in Life Sciences
The Acid-Sensitive, Anesthetic-Activated Potassium Leak Channel, Kcnk3, Is Regulated By 14-3-3beta-Dependent, Pkc-Mediated Endocytic Trafficking, Luke Gabriel, Anatoli Lvov, Demetra Orthodoxou, Ann Rittenhouse, William Kobertz, Haley Melikian
The Acid-Sensitive, Anesthetic-Activated Potassium Leak Channel, Kcnk3, Is Regulated By 14-3-3beta-Dependent, Pkc-Mediated Endocytic Trafficking, Luke Gabriel, Anatoli Lvov, Demetra Orthodoxou, Ann Rittenhouse, William Kobertz, Haley Melikian
Haley Melikian
The acid-sensitive neuronal potassium leak channel, KCNK3, is vital for setting the resting membrane potential and is the primary target for volatile anesthetics. Recent reports demonstrate that KCNK3 activity is downregulated by PKC; however, the mechanisms responsible for PKC-induced KCNK3 downregulation are undefined. Here, we report that endocytic trafficking dynamically regulates KCNK3 activity. Phorbol esters and Group I mGluR activation acutely decreased both native and recombinant KCNK3 currents with concomitant KCNK3 surface losses in cerebellar granule neurons and cell lines. PKC-mediated KCNK3 internalization required the presence of both 14-3-3beta and a novel potassium channel endocytic motif, as depleting either 14-3-3beta …
Dopamine Transporter Endocytic Trafficking In Striatal Dopaminergic Neurons: Differential Dependence On Dynamin And The Actin Cytoskeleton., Haley Melikian
Dopamine Transporter Endocytic Trafficking In Striatal Dopaminergic Neurons: Differential Dependence On Dynamin And The Actin Cytoskeleton., Haley Melikian
Haley Melikian
Dopaminergic signaling profoundly impacts rewarding behaviors, movement, and executive function. The presynaptic dopamine (DA) transporter (DAT) recaptures released DA, thereby limiting synaptic DA availability and maintaining dopaminergic tone. DAT constitutively internalizes and PKC activation rapidly accelerates DAT endocytosis, resulting in DAT surface loss. Longstanding evidence supports PKC-stimulated DAT trafficking in heterologous expression studies. However, PKC-stimulated DAT internalization is not readily observed in cultured dopaminergic neurons. Moreover, conflicting reports implicate both classic and nonclassic endocytic mechanisms mediating DAT trafficking. Prior DAT trafficking studies relied primarily upon chronic gene disruption and dominant-negative protein expression, or were performed in cell lines and cultured …
Nonclassical, Distinct Endocytic Signals Dictate Constitutive And Pkc-Regulated Neurotransmitter Transporter Internalization, Haley Melikian
Nonclassical, Distinct Endocytic Signals Dictate Constitutive And Pkc-Regulated Neurotransmitter Transporter Internalization, Haley Melikian
Haley Melikian
Neurotransmitter transporters are critical for synaptic neurotransmitter inactivation. Transporter inhibitors markedly increase the duration and magnitude of synaptic transmission, underscoring the importance of transporter activity in neurotransmission. Recent studies indicate that membrane trafficking dynamically governs neuronal transporter cell-surface presentation in a protein kinase C-regulated manner, suggesting that transporter trafficking profoundly affects synaptic signaling. However, the molecular architecture coupling neurotransmitter transporters to the endocytic machinery is not defined. Here, we identify nonclassical, distinct endocytic signals in the dopamine transporter (DAT) that are necessary and sufficient to drive constitutive and protein kinase C-regulated DAT internalization. The DAT internalization signal is conserved across …