3. Molecular and chemical aspects of the histamine receptors Molecular determinants of ligand-directed signaling for the histamine H_1 receptor

摘要

Histamine activation of the H_1 G protein-coupled receptor (GPCR) predominately activates Galpha_q protein and stimulation of phospholipase (PL) C to form inositol phosphates (IP) and diacylglycerol (DAG) signaling molecules . This activity can present as respiratory distress, diarrhea, edema, and hypotension associated with an allergic response. In mammalian brain and adrenal gland, H_1 activation also can stimulate Galpha_s and adenylyl cyclase (AC) to form adenosine 3',5'-cyclic monophosphate (cAMP), a signaling molecule that modulates catecholamine neurotransmitter synthesis and release . Development of H_1 drugs has focused on antagonists for then-anti-allergy effects. Recent understanding of the clinical importance of H_1 receptors in brain, however, suggests pharmacotherapeutic potential of H_1/AC/cAMP agonists in neurodegenerative and neuropsychiatric disorders . Like all mammalian GPCRs except bovine rhodopsin, the 3-dimensional structure of the human histamine H_1 receptor is unknown, compromising rational design of especially agonist H_1 receptor drugs. Here, human H_1 receptor mutagenesis and homology modeling results begin to delineate molecular determinants involved in histamine activation of H_1-mediated PLC/IP/ versus AC/cAMP signaling.