The α1 Subunit EGL-19, the α2/δ Subunit UNC-36, and the β Subunit CCB-1 Underlie Voltage-dependent Calcium Currents in Caenorhabditis elegans Striated Muscle

Lainé, Viviane; Frøkjær-Jensen, Christian; Couchoux, Harold; Jospin, Maëlle

doi:10.1074/jbc.m111.256149

Cited by 35 publications

(41 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nemadipine treatment (10 µM) completely blocked voltage-activated EGL-19/CaV1 calcium current in body muscles (Fig. S1A–B), confirming that Nemadipine is an effective EGL-19 antagonist (Laine et al, 2011). …”

Section: Resultssupporting

confidence: 62%

Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels

Tong

Soto

et al. 2017

Neuron

106

115

View full text Add to dashboard Cite

Summary The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post-synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/α2δ) decreasing UNC-36 abundance at pre-synaptic elements. Retrograde inhibition is mediated by a soluble form of NRX-1’s ectodomain, which is released from the post-synaptic membrane by the SUP-17/ADAM10 protease. Mammalian Neurexin-1α binds α2δ–3 and decreases CaV2.2 current in transfected cells whereas Neurexin-1α has no effect on CaV2.2 reconstituted with α2δ1 and α2δ2. Collectively, these results suggest that α-Neurexin binding to α2δ is a conserved mechanism for regulating synaptic transmission.

show abstract

Section: Resultssupporting

confidence: 62%

Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels

Tong

Soto

et al. 2017

Neuron

106

115

View full text Add to dashboard Cite

show abstract

“…Microdissection of C. elegans and electrophysiological methods were performed as described previously (Lainé et al, 2011). The resistance of recording pipettes ranged between 3 and 3.5 MU.…”

Section: Electrophysiologymentioning

confidence: 99%

C. elegans Punctin Clusters GABAA Receptors via Neuroligin Binding and UNC-40/DCC Recruitment

Pinan‐Lucarré

et al. 2015

Neuron

116

View full text Add to dashboard Cite

Positioning type A GABA receptors (GABA(A)Rs) in front of GABA release sites sets the strength of inhibitory synapses. The evolutionarily conserved Ce-Punctin/MADD-4 is an anterograde synaptic organizer that specifies GABAergic versus cholinergic identity of postsynaptic domains at the C. elegans neuromuscular junctions (NMJs). Here we show that the Ce-Punctin secreted by GABAergic motor neurons controls the clustering of GABA(A)Rs through the synaptic adhesion molecule neuroligin (NLG-1) and the netrin receptor UNC-40/DCC. The short isoform of Ce-Punctin binds and clusters NLG-1 postsynaptically at GABAergic NMJs. NLG-1 disruption causes a strong reduction of GABA(A)R content at GABAergic synapses. Ce-Punctin also binds and localizes UNC-40 receptors in the postsynaptic membrane of NMJs, which promotes the recruitment of GABA(A)Rs by NLG-1. Since the mammalian orthologs of these genes are expressed in the central nervous system and their mutations are implicated in neuropsychiatric diseases, this molecular pathway might have been evolutionarily conserved.

show abstract

“…R 200 , which represents the current fraction still present at the end of the pulse (Eqn 2), is higher in egl-19 (Lainé et al, 2011) and a recent study has also shown that the interaction between α 1 and α 2 -δ subunits is strong and that they are intimately associated at the plasma membrane (Cassidy et al, 2014). The expression of GFP:UNC-36 in unc-36 mutants rescued the locomotion phenotype and the Ca 2+ current defects observed in unc-36 mutants (Lainé et al, 2011;Zhan et al, 2014), so we assumed that the localization of the fusion protein matched that of endogenous channels. As previously described (Frøkjaer-Jensen et al, 2006), unc-36 staining was observed in most neuronal and muscle cells (Fig.…”

Section: Research Articlementioning

confidence: 99%

“…The fractional inactivation at the end of the pulse (R 200 ) and the time constant of activation (τ) were measured for the maximal current traces [at +20 mV for wild-type (N=15), +10 mV for egl-19(ad695) (N=15) and 0 mV for egl-19(n2368) (N=12)]. R 200 , which represents the current fraction still present at the end of the pulse (Eqn 2), is higher in egl-19 (Lainé et al, 2011) and a recent study has also shown that the interaction between α 1 and α 2 -δ subunits is strong and that they are intimately associated at the plasma membrane (Cassidy et al, 2014). The expression of GFP:UNC-36 in unc-36 mutants rescued the locomotion phenotype and the Ca 2+ current defects observed in unc-36 mutants (Lainé et al, 2011;Zhan et al, 2014), so we assumed that the localization of the fusion protein matched that of endogenous channels.…”

Section: Research Articlementioning

confidence: 99%

See 1 more Smart Citation

Hyperactivation of L-type voltage-gated Ca2+ channels in C. elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the α1 subunit.

Lainé

Ségor

Zhan

et al. 2014

Journal of Experimental Biology

Self Cite

View full text Add to dashboard Cite

Several human diseases, including hypokalemic periodic paralysis and Timothy syndrome, are caused by mutations in voltage-gated calcium channels. The effects of these mutations are not always well understood, partially because of difficulties in expressing these channels in heterologous systems. The use of Caenorhabditis elegans could be an alternative approach to determine the effects of mutations on voltage-gated calcium channel function because all the main types of voltage-gated calcium channels are found in C. elegans, a large panel of mutations already exists and efficient genetic tools are available to engineer customized mutations in any gene. In this study, we characterize the effects of two gain-of-function mutations in egl-19, which encodes the L-type calcium channel α 1 subunit. One of these mutations, ad695, leads to the replacement of a hydrophobic residue in the IIIS4 segment. The other mutation, n2368, changes a conserved glycine of IS6 segment; this mutation has been identified in patients with Timothy syndrome. We show that both egl-19 (gain-of-function) mutants have defects in locomotion and morphology that are linked to higher muscle tone. Using in situ electrophysiological approaches in striated muscle cells, we provide evidence that this high muscle tone is due to a shift of the voltage dependency towards negative potentials, associated with a decrease of the inactivation rate of the L-type Ca 2+ current. Moreover, we show that the maximal conductance of the Ca 2+ current is decreased in the strongest mutant egl-19(n2368), and that this decrease is correlated with a mislocalization of the channel.

show abstract

The α1 Subunit EGL-19, the α2/δ Subunit UNC-36, and the β Subunit CCB-1 Underlie Voltage-dependent Calcium Currents in Caenorhabditis elegans Striated Muscle

Cited by 35 publications

References 46 publications

Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels

Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels

C. elegans Punctin Clusters GABAA Receptors via Neuroligin Binding and UNC-40/DCC Recruitment

Hyperactivation of L-type voltage-gated Ca2+ channels in C. elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the α1 subunit.

Contact Info

Product

Resources

About