The cell adhesion protein CAR is a negative regulator of synaptic transmission

The Coxsackievirus and adenovirus receptor (CAR) is essential for normal electrical conductance in the heart, but its role in the postnatal brain is largely unknown. Using brain specific CAR knockout mice (KO), we discovered an unexpected role of CAR in neuronal communication. This includes increased basic synaptic transmission at hippocampal Schaffer collaterals, resistance to fatigue, and enhanced long-term potentiation. Spontaneous neurotransmitter release and speed of endocytosis are increased in KOs, accompanied by increased expression of the exocytosis associated calcium sensor synaptotagmin 2. Using proximity proteomics and binding studies, we link CAR to the exocytosis machinery as it associates with syntenin and synaptobrevin/VAMP2 at the synapse. Increased synaptic function does not cause adverse effects in KO mice, as behavior and learning are unaffected. Thus, unlike the connexin-dependent suppression of atrioventricular conduction in the cardiac knockout, communication in the CAR deficient brain is improved, suggesting a role for CAR in presynaptic processes

Cardiac deletion of the coxsackievirus-adenovirus receptor abolishes coxsackievirus b3 infection and prevents myocarditis in vivo

OBJECTIVES: We investigated the role of the Coxsackievirus-adenovirus receptor (CAR) in viral myocarditis. BACKGROUND: CAR is involved in virus uptake into various cell types. It has therefore been suggested as a therapeutic target to prevent or treat Coxsackievirus B3 (CVB3)-induced diseases such as myocarditis and cardiomyopathy. Recent work in CAR-deficient animals has indicated a role in embryonic development and remodeling with cardiac malformation and lethality. METHODS: We generated a tamoxifen-inducible knockout (KO) mouse to study CAR in the adult heart after CVB3 infection. Histomorphology, virus distribution, and cardiac function were compared in CAR-KO versus noninduced littermate control animals expressing wild-type CAR (WT). RESULTS: We have demonstrated that eliminating CAR prevents signs of inflammatory cardiomyopathy, with essentially no pathology in KO hearts. Unlike CVB3-infected WT control animals, the cardiac inducible KO mice did not exhibit structural changes such as monocyte infiltration or fibrosis after CVB3 infection or increased production of markers of inflammation such as interleukin-6 and -10. Whereas CVB3 infection resulted in severe contractile dysfunction in the hearts of animals that express WT, the CAR-deficient hearts appeared normal. CONCLUSIONS: Elimination of CAR in adult hearts can efficiently block virus entry and the associated pathology including contractile dysfunction. The lack of infiltration or other morphological changes in CVB3-infected KO hearts emphasizes the contribution of direct virus-mediated pathology in enteroviral myocarditis

Structurally defined zincated and aluminated complexes of ferrocene made by alkali-metal-synergistic syntheses

Reaction of ferrocene with 1 or 2 molar equiv of the synergistic-operative bimetallic sodium zincate base TMEDA·Na(μ-TMP)(μ-tBu)Zn(tBu) yields mainly mono- or dizincated complexes TMEDA·Na(μ-TMP)[μ-(C5H4)Fe(C5H5)]ZntBu (1) and [TMEDA·Na(μ-TMP)Zn(tBu)]2(C5H4)2Fe (2). Likewise, the separated pairing of Li(TMP) and (TMP)AliBu2 in the presence of THF can mono- or dimetalate ferrocene in a synergistic two-step lithiation/trans-metal-trapping protocol to give THF·Li(μ-TMP)[μ-(C5H4)Fe(C5H5)]Al(iBu)2 (4) or [THF·Li(μ-TMP)Al(iBu)2]2(C5H4)2Fe (5). In the absence of Lewis donating cosolvents, a 4-fold excess of the sodium zincate appears to produce an unprecedented 4-fold zincated ferrocene of formula Na4(TMP)4Zn4(tBu)4[(C5H3)2Fe] (3), whereas when donor solvent is withheld from the lithium/aluminum pairing, only dimetalation of ferrocene is possible. Tetrametalation seems to be inhibited by the in situ generation of TMP(H) via amido basicity, which then acts as a Lewis donor toward lithium, preventing inverse-crown formation and preferentially forming the Lewis acid–Lewis base adduct [TMP(H)·Li(μ-TMP)Al(iBu)2]2(C5H4)2Fe (6). With the exception of 3, all aforementioned complexes have been characterized by X-ray crystallography, while 1–6 have also been studied by solution NMR spectroscopic studies