Question

1) Explain the molecular mechanism of action of H1-receptor antagonists-

2) Explain the molecular mechanism of action of H2-receptor antagonists

Answer 1

H1 receptors are G protein coupled receptors (Gq) which operate through Phospholipase-IP3-DAG pathway. The agonist histamine binds to its H1 receptor and activates the G protein (Gq). Its alpha subunit binds GTP in place of GDP, dissociates from the receptor as well as from beta-gamma dimer to activate membrane bound phospholipase c that hydrolyses phosphatidyl inositol 4,5-bisphosphate (PIP2), a membrane bound phospholipid. The products IP3 and DAG acts as second messengers. The primary action of IP3 is facilitation of calcium mobilization from intracellular organellar pools, while DAG in addition to calcium also activates protein kinase C. Protein kinase C phosphorylates and alters the activity of a number of proteins. Cytosolic calcium is a veritable messenger: combines with calmodulin to activate myosin light chain kinase inducing the contraction, and another important regulator calcium calmodulin protein kinase. This is the molecular mechanism of action of histamine on H1 receptor. H1 RECEPTOR ANTAGONISTS COMPETITIVELY BIND TO H1 RECEPTOR AND PRODUCE NO RESPONSE. SO THE ABOVE MECHANISM WILL NOT OCCUR.

H2 Receptors are G protein coupled receptors (Gs) which operate through Adenylyl cyclase-cAMP pathway. Histamine binds to H2 receptor which permits interaction of G protein binding site with the stimulatory G protein (Gs). The activated alpha subunit of Gs now binds GTP and dissociates from the beta-gamma dimer as well as the receptor. The Gs alpha carrying bound GTP associates with and activates the enzyme adenylyl cyclase which hydrolyzes ATP to cAMP which then phosphorylates and thus activates cAMP dependent Protein kinase A. Protein kinase A phosphorylates many functional proteins like H-K ATPase Protein which gets activated. This removes one molecule of K and gives H ion and thus acid is secreted in the stomach. This action is ANTAGONIZED BY H2 BLOCKERS. THEY BIND TO H2 RECEPTOR AND BLOCK THIS PATHWAY and no acid is secreted.