The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a fulllength receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. We examined whether there are differential signaling properties attributable to the carboxyl terminus of this receptor by using stably transfected human embryonic kidney (HEK293) cell lines that express either full-length or truncated NK1R. Substance P (SP) specifically triggered intracellular calcium increase in HEK293 cells expressing full-length NK1R but had no effect in the cells expressing the truncated NK1R. In addition, in cells expressing full-length NK1R, SP activated NF-B and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-B, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKC␦ but inhibited phosphorylation of PKC␦ in cells expressing truncated NK1R. There are also differences in the timing of SPinduced ERK activation in cells expressing the two different forms of the receptor. Full-length NK1R activation of ERK was rapid (peak within 1-2 min), whereas truncated NK1R-mediated activation was slower (peak at 20 -30 min). Thus, the carboxyl terminus of NK1R is the structural basis for differences in the functional properties of the full-length and truncated NK1R. These differences may provide important information toward the design of new NK1R receptor antagonists.G protein-coupled receptor ͉ cell signaling ͉ Substance P ͉ truncated neurokinin-1 ͉ calcium mobilization

H epatitis C virus (HCV) is responsible for the vast majority of cases of transfusion-associated and community-acquired non-A, non-B hepatitis 1,2 and infects an estimated 170 million people worldwide. 3 The seroprevalence of anti-HCV antibody in the United States has been estimated at 1.8%, which corresponds to approximately 4 million people. 4 HCV is the leading cause of chronic viral hepatitis in the United States, 5 and HCV-infected individuals are the major recipients of liver transplantation. HCV, first molecularly cloned in 1989, 1 is a positive-strand RNA virus of the flavivirus family with a genome size of ϳ10 kb, which encodes a number of structural (core, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. 6 HCV has at least 6 distinct but related genotypes with more than 50 subtypes, and genotype 1 is the most common in the United States, Europe, and most parts of Asia. HCV typically escapes clearance by the host's immune system and leads to the establishment of a persistent infection in approximately 70% of infected individuals. 7 The consequences of a subset of patients with chronic HCV infection are cirrhosis, liver failure, and hepatocellular carcinoma. 8,9 Treatment of HCV with interferon alfa (IFN-␣) and ribavirin is associated with a sustained response rate of less than 50%. 7,10,11 These limited therapeutic efficacies and the absence of an effective HCV vaccine underscore the importance of research on factors that enhance HCV infection and compromise IFN-␣-based therapy.Alcohol is the most commonly used and abused drug in the United States. Alcohol abuse significantly affects morbidity and mortality from infectious diseases. 12 Alcohol consumption accelerates liver damage, diminishes therapeutic response to IFN-␣, and increases the rate of hepatocellular carcinoma in patients with chronic HCV

The chronicity of hepatitis C virus (HCV) infection raises the question of how HCV is able to persist in hepatic cells. We show that human primary hepatocytes and human hepatic cell lines (Huh7 and HepG2) spontaneously produce interferon (