Abstract
Connexin-36 (Cx36) electrical synapses strengthen transmission in a calcium/calmodulin (CaM)/calmodulin-dependent kinase II (CaMKII)-dependent manner similar to a mechanism whereby the N-methyl-D-aspartate (NMDA) receptor subunit NR2B facilitates chemical transmission. Since NR2B–microtubule interactions recruit receptors to the cell membrane during plasticity, we hypothesized an analogous modality for Cx36. We determined that Cx36 binding to tubulin at the carboxy-terminal domain was distinct from Cx43 and NR2B by binding a motif overlapping with the CaM and CaMKII binding motifs. Dual patch-clamp recordings demonstrated that pharmacological interference of the cytoskeleton and deleting the binding motif at the Cx36 carboxyl-terminal (CT) reversibly abolished Cx36 plasticity. Mechanistic details of trafficking to the gap-junction plaque (GJP) were probed pharmacologically and through mutational analysis, all of which affected GJP size and formation between cell pairs. Lys279, Ile280, and Lys281 positions were particularly critical. This study demonstrates that tubulin-dependent transport of Cx36 potentiates synaptic strength by delivering channels to GJPs, reinforcing the role of protein transport at chemical and electrical synapses to fine-tune communication between neurons.
Highlights
Synaptic plasticity at glutamatergic chemical synapses involves highly orchestrated molecular and morphological processes that fine-tune communication between neurons
Using the mouse Neuro-2a neuroblastoma cell line as a platform for exogenous expression of wild-type and mutant Cx36 proteins, we demonstrate that Cx36 binds tubulin through a conserved binding motif, which is distinct from the confirmed motif of Cx43 [20,21]
Cx36 Interaction with the Tubulin Cytoskeleton is Required for Electrical Plasticity
Summary
Synaptic plasticity at glutamatergic chemical synapses involves highly orchestrated molecular and morphological processes that fine-tune communication between neurons. Short- to long-term functional and morphological adaptations require dynamic trafficking and turnover of channel and receptor proteins. While the molecular machinery involved in chemical synaptic plasticity and the respective signaling network has been extensively investigated, fewer details are known about the plasticity of electrical synapses. Modifiable responses of electrical synapses have been found in both lower and higher vertebrates [1,2]. A phenomenon coined “run-up” was found to rapidly and profoundly strengthen gap-junctional conductance exclusively at Cx36 gap-junction plaques (GJPs); an observation later was shown to occur in a Ca2+ /calmodulin-dependent kinase. II (CaMKII)-dependent manner [3,4,5]. The Cx36 plasticity phenomenon parallels the interaction
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