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Query: UMLS:C0268596 (
EMA
)
2,520
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:C. elegans Punctin Clusters GABA(A) Receptors via Neuroligin Binding and UNC-40/DCC Recruitment. 2602 75
Punctin/
MADD
-4, a member of the ADAMTSL extracellular matrix protein family, was identified as an anterograde synaptic organizer in the nematode
Caenorhabditis elegans.
At GABAergic neuromuscular junctions, the
short isoform
MADD
-4B binds the ectodomain of neuroligin NLG-1, itself a postsynaptic organizer of inhibitory synapses. To identify the molecular bases of their partnership, we generated recombinant forms of the two proteins and carried out a comprehensive biochemical and biophysical study of their interaction, complemented by an
in vivo
localization study. We show that spontaneous proteolysis of
MADD
-4B first generates a shorter N-
MADD
-4B form, which comprises four thrombospondin (TSP) domains and one Ig-like domain and binds NLG-1. A second processing event eliminates the C-terminal Ig-like domain along with the ability of N-
MADD
-4B to bind NLG-1. These data identify the Ig-like domain as the primary determinant for N-
MADD
-4B interaction with NLG-1
in vitro
We further demonstrate
in vivo
that this Ig-like domain is essential, albeit not sufficient
per se
, for efficient recruitment of GABA
A
receptors at GABAergic synapses in
C. elegans
The interaction of N-
MADD
-4B with NLG-1 is also disrupted by heparin, used as a surrogate for the extracellular matrix component, heparan sulfate. High-affinity binding of heparin/heparan sulfate to the Ig-like domain may proceed from surface charge complementarity, as suggested by homology three-dimensional modeling. These data point to N-
MADD
-4B processing and cell-surface proteoglycan binding as two possible mechanisms to regulate the interaction between
MADD
-4B and NLG-1 at GABAergic synapses.
...
PMID:The Ig-like domain of Punctin/MADD-4 is the primary determinant for interaction with the ectodomain of neuroligin NLG-1. 3292 59
