Histamine is a well-known autacoid, which widely exists in vertebrate tissues and plays various roles. Its physiological functions depend on the activation of four types of histamine-related G protein-coupled receptors (H1R, H2R, H3R, H4R). Especially, H1R is expressed ubiquitously, which is involved in most histamine-induced allergic effects.
Previous functional studies reported that H1R mainly activates G_q protein, and the following optogenetical and chemical studies revealed that inhibition of histaminergic neurons induce acute non-REM sleep. However, recent studies suggested that H1R activates four types of G protein (G_s, G_i/o, G_q, and G_12/13), and thus the signaling axis for non-REM sleep remains elusive.
Structure-guided mutgenesis is a desirable tool for extracting specific signaling, which helps the understanding of the histamine signaling mechanism. Here, we determined the histamine-bound H1R-G_i structure at 3.4 Å resolution. This structure allowed clear assignment of histamine-H1R-G_i, which reveals the signaling axis of H1R-G_i. Moreover, our structure revealed that H1R adopts the G_i-specific binding mode, which differs from the G_q-coupled H1R structure reported previously.
Our results provide a molecular mechanism for the signal switch and a molecular basis for the further development of histamine drugs.