A Co-operative Regulation of Neuronal Excitability by UNC-7 Innexin and NCA/NALCN Leak Channel

Magali Bouhours,Hang Li,Wesley Hung,Mei Zhen,John Georgiou,John C Roder,Shangbang Gao,Michelle D Po

doi:10.1186/1756-6606-4-16

Magali Bouhours, Hang Li + Show 6 more

Open Access

https://doi.org/10.1186/1756-6606-4-16

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Abstract

Gap junctions mediate the electrical coupling and intercellular communication between neighboring cells. Some gap junction proteins, namely connexins and pannexins in vertebrates, and innexins in invertebrates, may also function as hemichannels. A conserved NCA/Dmα1U/NALCN family cation leak channel regulates the excitability and activity of vertebrate and invertebrate neurons. In the present study, we describe a genetic and functional interaction between the innexin UNC-7 and the cation leak channel NCA in Caenorhabditis elegans neurons. While the loss of the neuronal NCA channel function leads to a reduced evoked postsynaptic current at neuromuscular junctions, a simultaneous loss of the UNC-7 function restores the evoked response. The expression of UNC-7 in neurons reverts the effect of the unc-7 mutation; moreover, the expression of UNC-7 mutant proteins that are predicted to be unable to form gap junctions also reverts this effect, suggesting that UNC-7 innexin regulates neuronal activity, in part, through gap junction-independent functions. We propose that, in addition to gap junction-mediated functions, UNC-7 innexin may also form hemichannels to regulate C. elegans' neuronal activity cooperatively with the NCA family leak channels.

Highlights

Neuronal gap junction proteins mainly function at electrical synapses, where they form intercellular channels for ions and small molecules, such as second messengers, to flow bi-directionally, and sometimes directionally, allowing the coupled cells to synchronize their activities
Innexin unc-7 loss of function mutants do not display obvious synaptic transmission defects at neuromuscular junctions (NMJs) Defects associated with the unc-7 loss of function mutations, such as uncoordinated locomotion (Additional files 1 &2: Movies 1, 2), irregular active zone development and distribution along the nerve cords, and strong aldicarb resistance [42], all suggest a potential synaptic transmission deficit at NMJs
These results indicate that the locomotion phenotype, pharmacological response, as well as synaptic morphological defects of unc-7 mutants are unlikely to result from a simple deficit in synaptic transmission at NMJs

Summary

Introduction

Neuronal gap junction proteins mainly function at electrical synapses, where they form intercellular channels for ions and small molecules, such as second messengers, to flow bi-directionally, and sometimes directionally, allowing the coupled cells to synchronize their activities. While invertebrate gap junctions are composed exclusively of innexins, vertebrates possess two classes of gap junction proteins: connexins and pannexins [17]. The role of connexins in mediating electrical cell coupling in the central nervous system (CNS) has been extensively documented [18,19,20,21]. Some connexins play roles in cell differentiation (reviewed in [22]), adhesion and migration (reviewed in [23]) that may be independent of their channel activities. These extensively studied connexins are topologically similar to innexins, but share little primary sequence homology, and have likely evolved independently from innexins [17,24]. Pannexin-1 and Pannexin-2 are amongst the most abundant gap junction-forming proteins in the mammalian brain [17,25,26,27,28]

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