Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis

摘要

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 betweenSUMOconjugation and deconjugation to continuously and bidirectionally fine-tune the densities of two opposing conductances: the hyperpolarization activated current (I-h) and the transient potassium current (I-A). Second, tonic 5 nM dopamine (D-A) gated activity-dependent SUMOylation to permit and prevent activity-dependent regulation of I-h and I-A, 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 mu M 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.