TY - JOUR
T1 - Optical functionalization of human Class A orphan G-protein-coupled receptors
AU - Morri, Maurizio
AU - Sanchez-Romero, Inmaculada
AU - Tichy, Alexandra Madelaine
AU - Kainrath, Stephanie
AU - Gerrard, Elliot J.
AU - Hirschfeld, Priscila P.
AU - Schwarz, Jan
AU - Janovjak, Harald
PY - 2018/12/1
Y1 - 2018/12/1
N2 - G-protein-coupled receptors (GPCRs) form the largest receptor family, relay environmental stimuli to changes in cell behavior and represent prime drug targets. Many GPCRs are classified as orphan receptors because of the limited knowledge on their ligands and coupling to cellular signaling machineries. Here, we engineer a library of 63 chimeric receptors that contain the signaling domains of human orphan and understudied GPCRs functionally linked to the light-sensing domain of rhodopsin. Upon stimulation with visible light, we identify activation of canonical cell signaling pathways, including cAMP-, Ca2+-, MAPK/ERK-, and Rho-dependent pathways, downstream of the engineered receptors. For the human pseudogene GPR33, we resurrect a signaling function that supports its hypothesized role as a pathogen entry site. These results demonstrate that substituting unknown chemical activators with a light switch can reveal information about protein function and provide an optically controlled protein library for exploring the physiology and therapeutic potential of understudied GPCRs.
AB - G-protein-coupled receptors (GPCRs) form the largest receptor family, relay environmental stimuli to changes in cell behavior and represent prime drug targets. Many GPCRs are classified as orphan receptors because of the limited knowledge on their ligands and coupling to cellular signaling machineries. Here, we engineer a library of 63 chimeric receptors that contain the signaling domains of human orphan and understudied GPCRs functionally linked to the light-sensing domain of rhodopsin. Upon stimulation with visible light, we identify activation of canonical cell signaling pathways, including cAMP-, Ca2+-, MAPK/ERK-, and Rho-dependent pathways, downstream of the engineered receptors. For the human pseudogene GPR33, we resurrect a signaling function that supports its hypothesized role as a pathogen entry site. These results demonstrate that substituting unknown chemical activators with a light switch can reveal information about protein function and provide an optically controlled protein library for exploring the physiology and therapeutic potential of understudied GPCRs.
KW - Optical Functionalization
KW - Class A
KW - orphan G-protein-coupled
UR - http://www.scopus.com/inward/record.url?scp=85047086091&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04342-1
DO - 10.1038/s41467-018-04342-1
M3 - Article
C2 - 29769519
AN - SCOPUS:85047086091
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1950
ER -