Coxsackievirus and adenovirus receptor

Human CAR protein has a theoretical molecular weight of 40.0 kDa and is composed of 365 amino acids. The human CAR gene (CXADR) is found on chromosome 21. Alternative splicing is known to produce at least 2 splice variants known as hCAR1 and hCAR2 and are each composed of at least 7 exons. Pseudogenes of this gene are found on chromosomes 15, 18, and 21. The N-terminal segment comprises the two extracellular domains (D1 and D2). D1 is most distal from the membrane and contains a V/Ig-like fold whereas D2 is more proximal. The cytoplasmic tail of CAR contains the amino acids G S I V, which is characterized as a class 1 PDZ-binding motif for interacting with proteins containing PDZ domains. The protein is found to be expressed in various regions of the body including the heart, brain, and, more generally, epithelial and endothelial cells. Moreover, CAR expression is not found in normal or tumor cell lines. Expression of CAR in endothelial cells can be regulated by treatment with drugs. == Function ==

It functions as a homophilic and heterophilic cell adhesion molecule through its interactions with extracellular matrix glycoproteins such as: fibronectin, agrin, laminin-1 and tenascin-R. Cardiac CAR is essential for normal development of cardiomyocytes. The expression of CAR is high in developing tissues, including the heart and brain; postnatally it is expressed in epithelial cells and in adult cardiac muscle, it is localized at intercalated discs. Knocking out CAR is embryonic lethal in mice by day 11.5, coordinate with severe cardiac muscle abnormalities including left ventricular hyperplasia, sinuatrial valve abnormalities, pericardial edema, thoracic hemorrhaging, myocardial wall degeneration, regional apoptosis, reduced density and disorganization of myofibrils, and enlarged mitochondria. Cardiomyocyte-specific deletion of CAR after embryonic day 11 had no noticeable effect on development and postnatal life, suggesting that CAR is critical during a temporal window of cardiac development. Studies from human hearts have shown that lower expression of CXADR mRNA is associated with a risk allele at chromosome 21q21, which may in fact predispose hearts to arrhythmias. To discern the mechanistic underpinnings, hearts from heterozygous CAR knockout mice subjected to acute myocardial ischemia were evaluated and showed slowed ventricular conduction, earlier onset of ventricular arrhythmias, and increased susceptibility to arrhythmias. These findings were coordinate with a reduction in magnitude of the sodium current at intercalated discs; CAR coprecipitated with NaV1.5, which may provide a mechanistic link to this finding. Neural and lymphatic CAR is strongly expressed in the developing central nervous system where it is thought to mediate neurite outgrowth. In addition, expression of CAR is readily detectable in the adult nervous system. ==Clinical significance==

CAR is a receptor for both Coxsackie B virus and adenovirus 2 and 5, which are structurally distinct. In patients with myocarditis or dilated cardiomyopathy, elevated Coxsackie B2 viral nucleic acids have been detected in myocardial biopsy samples. Adenoviral genomic DNA has also been detected in myocardial biopsies of patients with idiopathic cardiomyopathy, or impaired left ventricular function of unknown origin. Patients exhibiting sudden death from acute myocardial infarction had a higher proportion of active coxsackie B virus infection relative to matched controls, which was coordinate with disrupted sarcolemmal localization of dystrophin, suggesting that enteroviral infection may worsen the outcome of patients with acute myocardial infarction. A role for CAR in arrhythmia susceptibility and ventricular fibrillation after myocardial infarction was shown in that CXADR lies near the 21q21 locus, which is strongly associated with these insults. == Interactions ==

CAR has been shown to interact with: MAGI-1b, NaV1.5 == References ==