Histamine H1 receptor

Allergy symptoms are mostly caused by the release of histamine in response to allergens. The binding of histamine to the extracellular portion of the H1 receptor triggers a structural change of the transmembrane portion, leading to a change in the C terminal area. This c terminal region interacts with G proteins, leading to the activation of the Gq signalling pathway, which triggers allergy symptoms like itchy eyes and runny noses. Many allergy drugs are anti-histamines, in that they bind to the histamine receptor but do not cause the conformational change that leads to a response. See also Receptor.

Structural highlights

The structure of the H1 histamine receptor bound to an antihistamine, doxepin was published in 2011 ^[1]. A view colors the N terminus blue and the C terminus red, with the intervening segments paralleling the rainbow (blue, green, yellow, orange, red). This image is oriented with the transmembrane section at the top and the cytosolic portion below. The are shown in grey, while hydrophilic amino acids are shown in purple.

was originally made as a tricyclic antidepressant, but it also is a potent antihistamine ^[2] binds among the transmembrane alpha helices. Binding is stabilized by a number of . Like many G protein coupled receptors, the bottom of the binding pocket contains a conserved residue. Interestingly, second generation antihistamines take advantage of an anion binding site formed by ; in this structure, they interact with a phosphate.

Like other G protein-coupled receptors, the Histamine H1 Receptor contains a (aspartate (D), arginine (R), tyrosine (Y)) motif in the seven helix transmembrane surface near . In some G protein receptors, an "ionic lock" interaction between the asparate and arginine in this motif stabilizes the inactive state^[3]; however, in the Histamine H1 receptor, Arginine 125 forms a hydrogen bond with , which stabilizes the inactive state.

A cryo-EM structure of the has been published. Histamine activates receptor via interacting with the key of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for Gq engagement. This can be seen by the farther distance between arginine 125 and Gln 416; they are now 2 angstroms farther apart.

See also:

• G protein-coupled receptor
• Receptor
• Transmembrane (cell surface) receptors
• Neurotransmitters