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Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis.
J Neurosci. 2019 01 23; 39(4):596-611.JN

Abstract

Neurons operate within defined activity limits, and feedback control mechanisms dynamically tune ionic currents to maintain this optimal range. This study describes a novel, rapid feedback mechanism that uses SUMOylation to continuously adjust ionic current densities according to changes in activity. Small ubiquitin-like modifier (SUMO) is a peptide that can be post-translationally conjugated to ion channels to influence their surface expression and biophysical properties. Neuronal activity can regulate the extent of protein SUMOylation. This study on the single, unambiguously identifiable lateral pyloric neuron (LP), a component of the pyloric network in the stomatogastric nervous system of male and female spiny lobsters (Panulirus interruptus), focused on dynamic SUMOylation in the context of activity homeostasis. There were four major findings: First, neuronal activity adjusted the balance between SUMO conjugation and deconjugation to continuously and bidirectionally fine-tune the densities of two opposing conductances: the hyperpolarization activated current (Ih) and the transient potassium current (IA). Second, tonic 5 nm dopamine (DA) gated activity-dependent SUMOylation to permit and prevent activity-dependent regulation of Ih and IA, respectively. Third, DA-gated, activity-dependent SUMOylation contributed to a feedback mechanism that restored the timing and duration of LP activity during prolonged modulation by 5 μm DA, which initially altered these and other activity features. Fourth, DA modulatory and metamoduatory (gating) effects were tailored to simultaneously alter and stabilize neuronal output. Our findings suggest that modulatory tone may select a subset of rapid activity-dependent mechanisms from a larger menu to achieve homeostasis under varying conditions.SIGNIFICANCE STATEMENT Post-translational SUMOylation of ion channel subunits controls their interactions. When subunit SUMOylation is dysregulated, conductance densities mediated by the channels are distorted, leading to nervous system disorders, such as seizures and chronic pain. Regulation of ion channel SUMOylation is poorly understood. This study demonstrated that neuronal activity can regulate SUMOylation to reconfigure ionic current densities over minutes, and this regulation was gated by tonic nanomolar dopamine. Dynamic SUMOylation was necessary to maintain specific aspects of neuronal output while the neuron was being modulated by high (5 μm) concentrations of dopamine, suggesting that the gating function may ensure neuronal homeostasis during extrinsic modulation of a circuit.

Authors+Show Affiliations

Department of Biology, and.Neuroscience Institute, Georgia State University, Atlanta, Georgia, 30303.Department of Biology, and dbaro@gsu.edu. Neuroscience Institute, Georgia State University, Atlanta, Georgia, 30303.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30504282

Citation

Parker, Anna R., et al. "Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 39, no. 4, 2019, pp. 596-611.
Parker AR, Forster LA, Baro DJ. Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis. J Neurosci. 2019;39(4):596-611.
Parker, A. R., Forster, L. A., & Baro, D. J. (2019). Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39(4), 596-611. https://doi.org/10.1523/JNEUROSCI.1379-18.2018
Parker AR, Forster LA, Baro DJ. Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis. J Neurosci. 2019 01 23;39(4):596-611. PubMed PMID: 30504282.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis. AU - Parker,Anna R, AU - Forster,Lori A, AU - Baro,Deborah J, Y1 - 2018/11/30/ PY - 2018/05/30/received PY - 2018/10/23/revised PY - 2018/11/03/accepted PY - 2018/12/7/pubmed PY - 2019/12/18/medline PY - 2018/12/4/entrez KW - HCN KW - KV4 KW - dopamine KW - metamodulation KW - short-term activity homeostasis KW - stomatogastric SP - 596 EP - 611 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 39 IS - 4 N2 - Neurons operate within defined activity limits, and feedback control mechanisms dynamically tune ionic currents to maintain this optimal range. This study describes a novel, rapid feedback mechanism that uses SUMOylation to continuously adjust ionic current densities according to changes in activity. Small ubiquitin-like modifier (SUMO) is a peptide that can be post-translationally conjugated to ion channels to influence their surface expression and biophysical properties. Neuronal activity can regulate the extent of protein SUMOylation. This study on the single, unambiguously identifiable lateral pyloric neuron (LP), a component of the pyloric network in the stomatogastric nervous system of male and female spiny lobsters (Panulirus interruptus), focused on dynamic SUMOylation in the context of activity homeostasis. There were four major findings: First, neuronal activity adjusted the balance between SUMO conjugation and deconjugation to continuously and bidirectionally fine-tune the densities of two opposing conductances: the hyperpolarization activated current (Ih) and the transient potassium current (IA). Second, tonic 5 nm dopamine (DA) gated activity-dependent SUMOylation to permit and prevent activity-dependent regulation of Ih and IA, respectively. Third, DA-gated, activity-dependent SUMOylation contributed to a feedback mechanism that restored the timing and duration of LP activity during prolonged modulation by 5 μm DA, which initially altered these and other activity features. Fourth, DA modulatory and metamoduatory (gating) effects were tailored to simultaneously alter and stabilize neuronal output. Our findings suggest that modulatory tone may select a subset of rapid activity-dependent mechanisms from a larger menu to achieve homeostasis under varying conditions.SIGNIFICANCE STATEMENT Post-translational SUMOylation of ion channel subunits controls their interactions. When subunit SUMOylation is dysregulated, conductance densities mediated by the channels are distorted, leading to nervous system disorders, such as seizures and chronic pain. Regulation of ion channel SUMOylation is poorly understood. This study demonstrated that neuronal activity can regulate SUMOylation to reconfigure ionic current densities over minutes, and this regulation was gated by tonic nanomolar dopamine. Dynamic SUMOylation was necessary to maintain specific aspects of neuronal output while the neuron was being modulated by high (5 μm) concentrations of dopamine, suggesting that the gating function may ensure neuronal homeostasis during extrinsic modulation of a circuit. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/30504282/Modulator_Gated_SUMOylation_Mediated_Activity_Dependent_Regulation_of_Ionic_Current_Densities_Contributes_to_Short_Term_Activity_Homeostasis_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=30504282 DB - PRIME DP - Unbound Medicine ER -