trans gauche

Figure 23.3 • Histamine rotamers.

hypersensitivity reactions is initiated by the interaction of an antigen-IgE complex with the membrane of a histamine storage cell. This interaction triggers activation of intracellular phosphokinase C (PKC), leading to accumulation of inositol phosphates, diacylglycerol, and calcium. Exocytotic release of histamine follows the degranulation of histamine storage cells.10 Degranulation also results in the release of other mediators of inflammation including prostaglandins, leukotrienes, platelet-activating factor, kinins, etc.10 The release of mast cell mediators can be inhibited by several agents as described in the sections that follow. Histamine is released from mast cells in the gastric mucosa by gastrin and acetylcholine. Neurochemical studies also suggest that histamine is stored in and released from selected neuronal tracts in the CNS.

Histamine Receptors and Histamine-Mediated Physiologic Functions

Once released, the physiological effects of histamine are mediated by specific cell-surface receptors. Extensive pharmacological and molecular biology studies have revealed the presence of at least four different histamine receptor subtypes in mammalian systems designated as Hi, H2, H3 and H4 (Table 23.1).10 All histamine receptor subtypes are heptahelical transmembrane molecules (TM1-TM7) that transduce extracellular signals via G-proteins to intracellular second-messenger systems. These receptors have constitu tive receptor G-protein-signaling activity that is independent of histamine agonist binding.1011 Thus, they exist in two conformations that are in equilibrium—an active (constitutive) and inactive state. The four histamine receptor subtypes differ in their expression, location, primary structure, precise signal transduction processes, and physiologic functions as indicated in Table 23.1 and detailed here. In general, H1- and H2-receptors appear to be more widely expressed than H3- and H4-receptors.10

Histamine H1-receptor expression is widespread including CNS neurons, the smooth muscle of respiratory, gastrointestinal (GI), uterine tissues, epithelial and endothelial cells, neutrophils, eosinophils, monocytes, dendritic cells, T cells, B cells, hepatocytes, and chondrocytes.10 This receptor is composed of 487 amino acids and has a molecular mass of 56 kd. Its seven transmembrane domains consist of a short intracellular C-terminal tail (17 amino acids), N-terminal glycosylation sites, phosphorylation sites for protein kinases A and C, and a large intracellular loop (212 amino acids, TM3).12,13 Based on data from site-directed mutagenesis studies, the third (TM3) and fifth (TM5) transmembrane domains are responsible for binding of H1-receptor ligands. An acidic aspartate residue in TM3 (position 107) appears to be responsible for binding of the protonated amino group of the ethylamine side chain of histamine via ionic interactions. An asparagine (position 207) of the TM5 domain appears to interact with the nT-nitrogen atom of the imidazole ring of histamine and lysine (200) interacts with the nucleophilic N nitrogen of the natural ligand.12,13

Signal transduction at the H1-receptor involves the activation of Gaq11 that stimulates intracellular phospholipase C (PLC) to hydrolyze phosphatidylinositide to inositol-1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). IP3 promotes intracellular calcium release, whereas DAG may stimulate various biochemical pathways including phospho-lipase A2 and D, NFtfB-mediated gene transcription, as well as cyclic adenosine monophosphate (cAMP) and nitric oxide synthase (NOS) production.10-13 Human H1-receptors have approximately 45% homology with muscarinic M1-and M2-receptors, perhaps accounting for some of the overlap in ligands bound by each receptor subtype. H1-receptor polymorphisms have been described, although it is not yet clear how they influence the histamine binding or clinical response to ^-antihistamine drugs.14

As a result of widespread tissue localization and the varied functions of these tissues, H1-receptors mediate a host of physiologic processes including pruritus, pain, vasodilation, vascular permeability, hypotension, flushing, headache, tachycardia, bronchoconstriction, stimulation of airway vagal

Figure 23.4 • Histamine biosynthesis.

TABLE 23.1 Histamine Receptor Subtypes






Receptor proteins

487 amino acids, 56 kd

359 amino acids, 40 kd

445 amino acids, 70 kd;

390 amino acids

in humans

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