The distribution and targeting of neuronal voltage-gated ion channels

Lai, Helen C.; Jan, Yuh Nung

doi:10.1038/nrn1938

Cited by 417 publications

(365 citation statements)

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“…This sorting of the major excitatory and inhibitory receptors in the somatodendritic region is reminiscent of the polarized trafficking of apical versus basolateral proteins in epithelial cells (45,46) and somatodendritic versus axonal proteins in neurons (47,48), which involves vesicular sorting in TGN and endosomes. Previous studies and our current research suggest a general strategy that proteins that function at different subdomains of the cell are sorted early into separate vesicle populations.…”

Section: Discussionmentioning

confidence: 99%

Differential vesicular sorting of AMPA and GABA _A receptors

Chiu

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In mature neurons AMPA receptors cluster at excitatory synapses primarily on dendritic spines, whereas GABA A receptors cluster at inhibitory synapses mainly on the soma and dendritic shafts. The molecular mechanisms underlying the precise sorting of these receptors remain unclear. By directly studying the constitutive exocytic vesicles of AMPA and GABA A receptors in vitro and in vivo, we demonstrate that they are initially sorted into different vesicles in the Golgi apparatus and inserted into distinct domains of the plasma membrane. These insertions are dependent on distinct Rab GTPases and SNARE complexes. The insertion of AMPA receptors requires SNAP25-syntaxin1A/B-VAMP2 complexes, whereas insertion of GABA A receptors relies on SNAP23-syntaxin1A/B-VAMP2 complexes. These SNARE complexes affect surface targeting of AMPA or GABA A receptors and synaptic transmission. Our studies reveal vesicular sorting mechanisms controlling the constitutive exocytosis of AMPA and GABA A receptors, which are critical for the regulation of excitatory and inhibitory responses in neurons.AMPA receptor | GABA A receptor | constitutive exocytosis | TIRFM | SNARE I n the mammalian central nervous system, neurons receive excitatory and inhibitory signals at synapses. Specific receptors at postsynaptic membranes are activated by neurotransmitters released by presynaptic terminals. Most fast excitatory neurotransmission is mediated by AMPA receptors, the majority of which are heterotetramers of GluA1/GluA2 or GluA2/GluA3 subunits in the hippocampus (1). Fast synaptic inhibition is largely mediated by GABA A receptors, which are predominantly heteropentamers of two α subunits, two β subunits, and one γ or δ subunit in the hippocampus (2). Numerous studies have demonstrated AMPA receptors are selectively localized at excitatory synapses on dendritic spines, whereas GABA A receptors cluster at inhibitory synapses localized on dendritic shafts and the soma (3). This segregation of excitatory and inhibitory receptors requires highly precise sorting machinery to target receptors to distinct synapses opposing specific presynaptic terminals. However, it is still not clear whether the receptors are sorted before exocytosis into the plasma membrane or are differentially localized only after exocytosis. For example in a "plasma membrane sorting model," different receptors could be pooled into the same vesicle and inserted along the somatodendritic membrane. The initial sorting would occur on the plasma membrane, where inserted receptors would be segregated by lateral diffusion and stabilization at different postsynaptic zones. Alternatively, in a "vesicle sorting model," different receptors would first be sorted into different vesicles during intracellular trafficking processes and independently inserted to the plasma membrane, where receptors could be further targeted to specific zones and stabilized by synaptic scaffolds. To date there has been no direct evidence to support either model. However, a large body of literature suggests that the e...

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Section: Discussionmentioning

confidence: 99%

Differential vesicular sorting of AMPA and GABA _A receptors

Chiu

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, it is still uncertain how receptors and ion channels are targeted to more confined areas within the dendrites, such as proximal dendrites, distal dendrites, and dendritic spines (5).…”

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confidence: 99%

Specific Sorting and Post-Golgi Trafficking of Dendritic Potassium Channels in Living Neurons

Jensen

Watanabe

Rasmussen

et al. 2014

Journal of Biological Chemistry

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“…ion channel trafficking ͉ early endosome ͉ cardiac myocytes ͉ small conductance Ca 2ϩ -activated K ϩ channel ͉ calmodulin binding domain T he function of ion channels depends critically on the precise number and subcellular localization of the channel proteins on the cell-surface membrane (1,2). The steady-state cell-surface expression of ion channels is intricately and dynamically governed by the anterograde (forward) and retrograde trafficking (2,3).…”

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confidence: 99%

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

Lü

Timofeyev

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The importance of proper ion channel trafficking is underpinned by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface. Conceptually, it is reasonable to suggest that the function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane, which is determined jointly by the secretory and endocytic pathways. Yet the precise mechanisms of the entire ion channel trafficking pathway remain unknown. Here, we directly demonstrate that proper membrane localization of a smallconductance Ca 2ϩ -activated K ؉ channel (SK2 or KCa2.2) is dependent on its interacting protein, ␣-actinin2, a major F-actin crosslinking protein. SK2 channel localization on the cell-surface membrane is dynamically regulated, and one of the critical steps includes the process of cytoskeletal anchoring of SK2 channel by its interacting protein, ␣-actinin2, as well as endocytic recycling via early endosome back to the cell membrane. Consequently, alteration of these components of SK2 channel recycling results in profound changes in channel surface expression. The importance of our findings may transcend the area of K ؉ channels, given that similar cytoskeletal interaction and anchoring may be critical for the membrane localization of other ion channels in neurons and other excitable cells.ion channel trafficking ͉ early endosome ͉ cardiac myocytes ͉ small conductance Ca 2ϩ -activated K ϩ channel ͉ calmodulin binding domain T he function of ion channels depends critically on the precise number and subcellular localization of the channel proteins on the cell-surface membrane (1, 2). The steady-state cell-surface expression of ion channels is intricately and dynamically governed by the anterograde (forward) and retrograde trafficking (2, 3). Ion channel molecules are first synthesized in the endoplasmic reticulum (ER), assembled and processed, then trafficked to the membrane where they function. Trafficking of ion channel proteins to the surface membrane involves a series of tightly regulated events coordinated by ER resident proteins, microtubules, transport vesicle and Golgi apparatus, the actin cytoskeleton, myosins, and anchoring proteins (2). The importance of correct ion channel trafficking is highlighted by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface (4-8).Small-conductance Ca 2ϩ -activated K ϩ (SK or K Ca 2) channels belong to a family of Ca 2ϩ -activated K ϩ channels (K Ca ) that have been reported from a wide variety of cells (9-11). SK channels represent a highly unique family of K ϩ channels, in that they are directly gated by changes in intracellular Ca 2ϩ concentration and hence function to integrate changes in Ca 2ϩ concentration with changes in K ϩ conductance and membrane potentials. SK channels have been shown to mediate afterhyperpolarizations in neurons (9, 12, 13) and action potential repolarization in cardiac tissues (14,15). Prev...

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The distribution and targeting of neuronal voltage-gated ion channels

Cited by 417 publications

References 205 publications

Differential vesicular sorting of AMPA and GABA _A receptors

Differential vesicular sorting of AMPA and GABA _A receptors

Specific Sorting and Post-Golgi Trafficking of Dendritic Potassium Channels in Living Neurons

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

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The distribution and targeting of neuronal voltage-gated ion channels

Cited by 417 publications

References 205 publications

Differential vesicular sorting of AMPA and GABA A receptors

Differential vesicular sorting of AMPA and GABA A receptors

Specific Sorting and Post-Golgi Trafficking of Dendritic Potassium Channels in Living Neurons

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+channel (SK2 channel)

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Differential vesicular sorting of AMPA and GABA _A receptors

Differential vesicular sorting of AMPA and GABA _A receptors

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)