CPLX1

Complexin-1, the protein product of the CPLX1 gene, is a soluble cytosolic protein that participates in the regulation of synaptic vesicle exocytosis. It associates with the assembled SNARE complex and interacts with crucial components such as SNAP25 and syntaxin-1A (STX1A). Through these interactions, complexin-1 influences the stability and configuration of the SNARE machinery that drives vesicle fusion.^[5]

CPLX1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3RK3, 3RL0
Identifiers
Aliases	CPLX1, CPX-I, CPX1, complexin 1, EIEE63, DEE63
External IDs	OMIM: 605032; MGI: 104727; HomoloGene: 21324; GeneCards: CPLX1; OMA:CPLX1 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4p16.3 Start 784,957 bp[1] End 826,129 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 F Start 108,666,420 bp[2] End 108,697,890 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lateral nuclear group of thalamus external globus pallidus postcentral gyrus pons superior frontal gyrus right frontal lobe putamen primary visual cortex right hemisphere of cerebellum caudate nucleus Top expressed in motor neuron substantia nigra facial motor nucleus pontine nuclei lateral geniculate nucleus medial vestibular nucleus habenula anterior horn of spinal cord medial geniculate nucleus deep cerebellar nuclei More reference expression data BioGPS More reference expression data
Gene ontology Molecular function syntaxin-1 binding neurotransmitter transmembrane transporter activity syntaxin binding SNARE binding protein binding Cellular component cytoplasm cytosol synapse synaptobrevin 2-SNAP-25-syntaxin-3-complexin complex synaptobrevin 2-SNAP-25-syntaxin-1a-complexin I complex soma dendrite SNARE complex protein-containing complex presynapse calyx of Held Schaffer collateral - CA1 synapse postsynapse glutamatergic synapse terminal bouton Biological process synaptic vesicle exocytosis insulin secretion regulation of exocytosis neurotransmitter transport exocytosis chemical synaptic transmission regulation of synaptic vesicle fusion to presynaptic active zone membrane exocytic insertion of neurotransmitter receptor to postsynaptic membrane vesicle-mediated transport in synapse regulation of neurotransmitter secretion neurotransmitter secretion glutamate secretion Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10815 12889 Ensembl ENSG00000168993 ENSMUSG00000033615 UniProt O14810 P63040 RefSeq (mRNA) NM_006651 NM_007756 RefSeq (protein) NP_006642 NP_031782 Location (UCSC) Chr 4: 0.78 – 0.83 Mb Chr 5: 108.67 – 108.7 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

In the late stages of exocytosis, complexin-1 helps control the release of both synaptic and other secretory vesicles. Structural studies indicates that it can organize SNARE proteins into an ordered, cross-linked arrangement that temporarily blocks full membrane fusion. This "clamp-like" function prevents vesicles from fusing prematurely and ensures that neurotransmitter release occurs only in response to an incoming action potential. Beyond the nervous system, complexin-1 also contributes to regulated secretion in pancreatic beta-cells, where it supports glucose-stimulated insulin release. Proper complexin-1 function is required for normal synaptic transmission and is important for maintaining coordinated motor behavior.^[5]

Gene

Orthologs

CPLX1 is widely conserved across vertebrates and plays a similar role in regulating synaptic vesicle release in many species. Human CPLX1^[6], located on chromosome 4p16.3,^[5] has direct orthologs in mammals such as a mouse and rat, where the corresponding Clpx1 gene produces complexin-1 proteins involved in neurotransmission. More than 190 species possess identifiable orthologs of the human gene, reflecting the evolutionary importance of complexin-mediated control of the SNARE complex.

In mice^[7], Clpx1 is essential for normal neural function, and the absence of the gene results in pronounced motor coordination deficits, changes in social behavior, and abnormalities in early development. The rat Clpx1 gene^[8] encodes a comparable protein that participates in presynaptic signaling. Orthologous genes are also found in a broad range of other vertebrates -- including Rhesus macaque, dog, cow, chicken, frog, and zebrafish^[5] -- suggesting that complexin-1's regulatory role in exocytosis has been maintained throughout vertebrate evolution.

Paralogs

The CPLX1 gene belongs to a complexin family, which in humans includes three additional paralogs: CPLX2, CPLX3, and CPLX4.^[9] All four genes encode small cytosolic proteins that regulate synaptic vesicle fusion by interacting with components of the SNARE complex, but each paralog shows distinct expression patterns and functional specializations.

CPLX1 encodes complexin-1, a protein best known for its role in modulating neurotransmitter release at central nervous system synapses. CPLX2, which encodes complexin-2, is the paralog most closely related to CPLX1 and is frequently studied in parallel. Like complexin-1, complexin-2 participates in presynaptic regulation, though the expression profile partially differs across neuronal populations. CPLX3 and CPLX4 form a separate subgroup within the family and are expressed more selectively. Both are found at high levels in the retina, whereas they show limited or no expression in certain brainstem regions such as the medical nucleus of the trapezoid body (MNTB), where CPLX1 is the dominant isoform.^[9]

Protein

Complexin-1 is composed of 134 amino acids with an approximate molecular mass of 15 kDa. The UniProt accession number for human complexin-1 is O14810, with several additional secondary accession identifiers reported (A6NI80, B2R4R5, D3DVN3, and F1T0G1). The protein is classified at evidence level PE1, indicating confirmed existence at the protein level. Complexin-1 interacts directly with the SNARE core complex binding to assemblies that include SNAP25, VAMP2, and syntaxin-1A (STX1A), which facilitates its role in regulating synaptic vesicle fusion.^[9]

Function

Communication between neurons depends on the precise release of neurotransmitters through a tightly regulated fusion process. Before a vesicle can merge with the plasma membrane, a set of membrane associated proteins must assemble into a SNARE complex. In this initial step, syntaxin and SNAP25 on the presynaptic membrane pair with the vesicle protein synaptobrevin to form a stable bundle that drives enzymes NSF, which disassembles the SNARE complex and resets the system for another cycle. The calcium-sensing protein synaptoagmin then coordinates the final stage of fusion, ensuring that exocytosis is linked to a rise in intracellular Ca${\displaystyle {\ce {2+}}}$ during neuronal activity.^[10]

Complexin-1, encoded by CPLX1, acts as a regulatory partner of the SNARE machinery. Structural studies have revealed that complexin-1 binds to an assembling SNARE complex and stabilizes it in a partially zippered state. Its central alpha-helical domain lies along one SNARE bundle, while an accessory region extends outward toward an adjacent SNARE assembly. This arrangement creates a cross-linked pattern of SNARE complexes that is incompatible with complete C-terminal zippering, thereby halting membrane fusion until the appropriate signal arrives.^[11]

Although complexin-1 can block premature vesicle fusion, it also promotes neurotransmitter release once Ca${\displaystyle {\ce {2+}}}$ levels rise. Its N-terminal region supports synchronous Ca${\displaystyle {\ce {2+}}}$ - evoked exocytosis while other domains help restrain spontaneous release under resting conditions. In this way, complexin-1 functions as both a clamp and an enhancer, allowing vesicles to remain primed without fusing until the arrival of an action potential.^[12]

CPLX1 is highly enriched in inhibitory synapses and contributes to the accuracy and timing of synaptic responses. Loss-of-function experiments in animal models show that the absence of complexin-1 alters neurotransmitter release dynamics and leads to motor coordination deficits, social interaction abnormalities, and increased anxiety-like behaviors, pointing to a broad influence on neural activity.^[12] Complexin-1 also participates in exocytosis outside the nervous system including regulated secretion in pancreatic beta-cells -- where it is required for proper insulin release -- and in specialized secretory events such as sperm acrosome exocytosis.^[12]

Disruptions in CPLX1 expression or function have been associated with several neuropsychiatric conditions, including schizophrenia and depression.^[12] Some variants may weaken complexin-1's inhibitory capacity, allowing excessive spontaneous neurotransmitter release.^[13] Regulatory pathways influenced by neuronal activity, including miRNA-based mechanism can modify CPLX1 expression levels and in turn alter presynaptic function and behavior.^[12]

Interactions

CPLX1 is associated with several components of the presynaptic fusion machinery, primarily through its binding to the assembled SNARE complex. The protein interacts with syntaxin-1A and SNAP25, and binds synaptobrevin only when it is incorporated into the full SNARE bundle rather than an isolated molecule. Complexin-1 also engages with synaptotagmin I, the Ca${\displaystyle {\ce {2+}}}$ sensor for exocytosis, but does not bind alpha-SNAP or other SNAP family members. These interactions position CPLX1 as a regulator or SNARE-complex dynamics during synaptic vesicle fusion.^[14]