Prostaglandin E2 (PGE2) is involved in a number of physiologic and pathophysiologic events in many tissues of the body. The biologic effects of PGE2 are mediated through interaction with specific membrane-bound G protein-coupled prostanoid EP receptors. EP3 receptor (or PTGER3) is expressed as multiple transcripts through alternative splicing, with each transcript showing a different tissue-specific distribution. PGE2 may mediate fever generation in response to both endogenous and exogenous pyrogens by acting at the EP3 receptor. EP3-mediated neuronal pathways converge at corticotropin-releasing hormone containing neurons in the paraventricular nucleus of the hypothalamus to induce HPA axis activation during sickness. At cellular level, EP3 has been shown to couple to both Gs and Gi/o types of the heterotrimeric G proteins to stimulate or inhibit intracellular cAMP synthesis. This cell line does not respond to pertussis toxin (PTX) treatment, indicating its coupling to Gi/o proteins is insignificant.