Changes in ₂-adrenergic receptor (₂-AR) gene expression in the rat liver during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats exhibit two metabolically distinct phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis). The [³H]dihydroalprenolol binding studies show that the density of ₂-AR was decreased by 12 and 35% during the early and late phases of sepsis, respectively. Western blot analyses depict that the ₂-AR protein level was reduced by 37 and 72% during early and late sepsis, respectively. The reverse transcription polymerase chain reaction and Southern blot analyses reveal that the steady-state level of ₂-AR mRNA was decreased by 37% during early phase and 77% during late phase of sepsis. Nuclear run-off assays show that the rate of transcription of ₂-AR mRNA was reduced by 36% during early sepsis and 64% during late sepsis. The stability assays indicate that the half-life of ₂-AR mRNA was shortened by 21 and 50% during the early and late phases of sepsis, respectively, indicating that the rate of degradation of ₂-AR mRNA was progressively enhanced during sepsis. These findings demonstrate that the ₂-AR gene was underexpressed in the liver during the progression of sepsis, and, furthermore, the underexpression of the ₂-AR gene was the result of a reduction in the rate of transcription coupled with an enhancement in the rate of degradation of ₂-AR gene transcripts. Thus our findings that the transcriptional and posttranscriptional regulation of ₂-AR gene associated with decreases in ₂-AR number and its protein expression may provide a molecular mechanistic explanation for the development of hypoglycemia during the late stage of sepsis.