Disease relevance of Cplx1

• Cplx1-/- mice show pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia and resting tremor [1].

Psychiatry related information on Cplx1

• A similar impairment in CA3 mossy fibre LTP in the R6/2 mouse model of Huntington's disease and in the complexin II knockout mouse [2].
• Vulnerability of synaptic plasticity in the complexin II knockout mouse to maternal deprivation stress [3].
• We examined the physiological characteristics of complexin II gene-deficient mice subjected to maternal deprivation stress to determine whether psychological stress during the early stage of life affected the development of brain function [3].

High impact information on Cplx1

• Here, we characterize the behavioural phenotype of Cplx1 knockout (Cplx1-/-) mice [1].
• Cplx1-/- mice develop a strong ataxia in the absence of cerebellar degeneration [1].
• Complexin, also known as synaphin, is a neuronal cytosolic protein that acts as a positive regulator of synaptic vesicle exocytosis [4].
• We propose that complexin facilitates neuronal exocytosis by promoting interaction between the complementary syntaxin and synaptobrevin transmembrane regions that reside in opposing membranes prior to fusion [4].
• Overexpression of CPX I or silencing of the CPX I gene (Cplx1) by RNA interference led to strong impairment in beta-cell secretion in response to nutrients such as glucose, leucine and KCl [5].

Biological context of Cplx1

• Although the abnormal motor phenotype dominates their overt symptoms, Cplx1-/- mice also show other behavioural deficits, particularly in complex behaviours [1].
• Complexin binds selectively to the neuronal SNARE complex, but how this promotes exocytosis remains unknown [4].
• Through screening of a murine brain cDNA library, we have isolated two brain specific cDNAs encoding highly homologous proteins, named 921-L and 921-S, comprised of 134 amino acids with 80% identity [6].
• Surface biotinylation demonstrated that the complexin-induced reduction in basal I(sc)was due to a reduction in apical membrane-resident ENaC and the inhibition in forskolin stimulation was due to the lack of ENaC insertion into the apical membrane to increase surface channel number [7].
• The long-term potentiation (LTP) by high-frequency stimulation, recorded in the hippocampal CA1 area, was decreased in complexin II-lacking mice (CPXII KO mice) [8].

Anatomical context of Cplx1

• Complexin I regulates glucose-induced secretion in pancreatic beta-cells [5].
• Short-circuit current (I(sc)) measurements on mCCD cell lines stably over- or underexpressing complexin produced similar results [7].
• A novel SNARE-binding protein, complexin, has been identified in nervous tissue which specifically binds to and stabilizes SNARE complexes at synaptic membranes to promote vesicle fusion [7].
• Here we describe the specific and progressive loss of complexin II from the brains of mice carrying the HD mutation (R6/2 line), and the later appearance of this protein in a subpopulation of neuronal intranuclear inclusions [9].
• Complexin II mRNA coexpressed with alpha-, beta-, and gamma-ENaC subunits in Xenopus laevis oocytes reduced sodium currents to 16 +/- 3% (n = 19) of control values [7].

Physical interactions of Cplx1

• Here we used purified full-length and truncated SNARE proteins and a gel shift assay to show that the action of complexin on SNARE complex depends strictly on the transmembrane regions of syntaxin and synaptobrevin [4].

Other interactions of Cplx1

• Mice lacking complexin II (Cplx2-/- mice) show selective cognitive deficits that reflect those seen in R6/2 mice [2].
• Complexin II is reduced in Huntington's disease (HD) patients and in the R6/2 mouse model of HD [2].
• When the calcium sensor synaptotagmin is added in the presence of calcium, inhibition by complexin is relieved and full fusion rapidly proceeds [10].

References