β-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment

Yang, Sungchil; Ben-Shalom, Roy; Ahn, Misol; Liptak, Alayna T.; Rijn, Richard M. van; Whistler, Jennifer L.; Bender, Kevin J.

doi:10.1016/j.celrep.2016.06.098

Cited by 29 publications

(50 citation statements)

References 53 publications

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“…7, but see Yu et al, 2010), channel modulation occurred only in D3R-expressing neurons, identified either through fluorescent tag (D3-Cre::Ai14) or electrophysiological identification (Type 3). Modulation was restricted to AIS-localized Ca V 3 channels, consistent with previous findings in D3R-expressing auditory brainstem neurons (Bender et al, 2010(Bender et al, , 2012Yang et al, 2016). Within these neurons, we observed a marked reduction of both evoked and spontaneous bursts (Bender and Trussell, 2009;Bender et al, 2012).…”

Section: Implications For Mpfc D3 Receptor Function In Health and Dissupporting

confidence: 79%

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D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells

Clarkson¹,

Liptak²,

Gee³

et al. 2017

J. Neurosci.

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102

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The D3 dopamine receptor, a member of the G i -coupled D2 family of dopamine receptors, is expressed throughout limbic circuits affected in neuropsychiatric disorders, including prefrontal cortex (PFC). These receptors are important for prefrontal executive function because pharmacological and genetic manipulations that affect prefrontal D3 receptors alter anxiety, social interaction, and reversal learning. However, the mechanisms by which D3 receptors regulate prefrontal circuits and whether D3 receptors regulate specific prefrontal subnetworks remains unknown. Here, we combine dopamine receptor reporter lines, anatomical tracing techniques, and electrophysiology to show that D3 receptor expression defines a novel subclass of layer 5 glutamatergic pyramidal cell in mouse PFC (either sex). D3-receptor-expressing pyramidal neurons are electrophysiologically and anatomically separable from neighboring neurons expressing D1 or D2 receptors based on their dendritic morphology and subthreshold and suprathreshold intrinsic excitability. D3-receptorexpressing neurons send axonal projections to intratelencephalic (IT) targets, including contralateral cortex, nucleus accumbens, and basolateral amygdala. Within these neurons, D3 receptor activation was found to regulate low-voltage-activated Ca V 3.2 calcium channels localized to the axon initial segment, which suppressed action potential (AP) excitability, particularly when APs occurred at high frequency. Therefore, these data indicate that D3 receptors regulate the excitability of a unique, IT prefrontal cell population, thereby defining novel circuitry and cellular actions for D3 receptors in PFC.

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Section: Implications For Mpfc D3 Receptor Function In Health and Dissupporting

confidence: 79%

“…In previous work in auditory brainstem, we found that D3Rs specifically modulate Ca V 3 calcium channels (Bender et al, 2010;Yang et al, 2016). Here, we found that AIS Ca was modulated only in D3ϩ/Type 3 cells.…”

Section: D3rs Are Expressed In a Distinct Subset Of Mpfc Pyramidal Cellsmentioning

confidence: 42%

D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells

Clarkson¹,

Liptak²,

Gee³

et al. 2017

J. Neurosci.

Self Cite

102

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“…S9). Longer activation of the receptor evokes stable binding of β-arrestin and augments ERK signaling, a molecular mechanism that could be involved in modulation of ion channels (46,47) and formation of long-term memories (30,39,48). Evidently, by itself β-arrestin 1, but not β-arrestin 2, can act directly on plasma membrane ion channels (49).…”

Section: Discussionmentioning

confidence: 99%

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

Jung

Kushmerick

Seo

et al. 2017

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

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Binding of agonists to G-protein-coupled receptors (GPCRs) activates heterotrimeric G proteins and downstream signaling. Agonistbound GPCRs are then phosphorylated by protein kinases and bound by arrestin to trigger desensitization and endocytosis. Arrestin plays another important signaling function. It recruits and regulates activity of an extracellular signal-regulated kinase (ERK) cascade. However, molecular details and timing of ERK activation remain fundamental unanswered questions that limit understanding of how arrestin-dependent GPCR signaling controls cell functions.Here we validate and model a system that tracks the dynamics of interactions of arrestin with receptors and of ERK activation using optical reporters. Our intermolecular FRET measurements in living cells are consistent with β-arrestin binding to M 1 muscarinic acetylcholine receptors (M 1 Rs) in two different binding modes, transient and stable. The stable mode persists for minutes after agonist removal. The choice of mode is governed by phosphorylation on key residues in the third intracellular loop of the receptor. We detect a similar intramolecular conformational change in arrestin in either binding mode. It develops within seconds of arrestin binding to the M 1 receptor, and it reverses within seconds of arrestin unbinding from the transient binding mode. Furthermore, we observed that, when stably bound to phosphorylated M 1 R, β-arrestin scaffolds and activates MEK-dependent ERK. In contrast, when transiently bound, β-arrestin reduces ERK activity via recruitment of a protein phosphatase. All this ERK signaling develops at the plasma membrane. In this scaffolding hypothesis, a shifting balance between the two arrestin binding modes determines the degree of ERK activation at the membrane.arrestin | GPCR | ERK | muscarinic receptor | receptor kinase A rrestin plays a fundamental role in the negative regulation of G-protein-coupled receptors (GPCRs) signaling because its binding to GPCRs hinders G-protein association with the receptors (1-5). Arrestin further recruits adaptor proteins and clathrin for the internalization and desensitization of the receptor (6). Additional functions have been suggested, with β-arrestin producing its own signaling through interactions with other effectors (7-9). For example, β-arrestin has binding sites for cRaf (MAPK kinase kinase), MEK (MAPK kinase), and ERK (MAPK) that mediate a signaling cascade for cell proliferation, cell migration, and actin dynamics after GPCR activation (10-13). Conventionally, MEK-dependent ERK signaling is described as involving GPCR-arrestin complexes on intracellular compartments such as endosomal vesicles (10, 14-16). However, whether similar complexes at the plasma membrane might trigger ERK signaling remains unknown. Electron microscope images of arrestin-receptor complexes together with modeling suggest that β-arrestin binds in two different modes, called transient binding and stable binding, to chimeric β 2 adrenergic receptors (β 2 -AR) containing the C terminus of vasopre...

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“…Converging lines of evidence suggest that the AIS is a highly dynamic structure, exhibiting structural plasticity over different timescales ranging from a few hours to several days (7)(8)(9)(10)(11)(12)(13)(29)(30)(31). Various elegant studies used typical triggers of plasticity such as sensory deprivation, optogenetic stimulation, or high-K + -induced depolarization (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…Long considered to be the trigger zone for AP initiation (28), the AIS was regarded as a static and rigid structure encompassing ion channels anchored to a scaffolding and cytoskeletal protein network. Now, it is recognized that the AIS is a highly dynamic structure, capable of structural and functional plasticity and continuously adapting to changes in neuronal activity (8,12,(29)(30)(31). In 2010, two seminal studies found that changes in neuronal activity could lead to AIS relocation or resizing as a new mechanism of slow homeostatic adaptation (32,33).…”

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confidence: 99%

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

Lezmy

Lipinsky

Khrapunsky

et al. 2017

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

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Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M-type K + channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability. Dual soma-axon patch-clamp recordings combined with axonal Na + imaging and immunocytochemistry revealed that these compensatory alterations were associated with a distal shift of the spike trigger zone and distal relocation of FGF14, Na + , and K v 7 channels but not ankyrin G. The concomitant distal redistribution of FGF14 together with Na v and K v 7 segments along the AIS suggests that these channels relocate as a structural and functional unit. These fast homeostatic changes were independent of L-type Ca 2+ channel activity but were contingent on the crucial AIS protein, protein kinase CK2. Using compartmental simulations, we examined the effects of varying the AIS position relative to the soma and found that AIS distal relocation of both Na v and K v 7 channels elicited a decrease in neuronal excitability. Thus, alterations in M-channel activity rapidly trigger unique AIS plasticity to stabilize network excitability.homeostatic plasticity | axon initial segment | M-current | potassium channel | K v 7

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β-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment

Cited by 29 publications

References 53 publications

D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells

D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

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