Production of
cAMP in response to activation of
TDAG8 G protein-coupled receptor by low
pH. Data from Wang et al., "TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor".[1]
Proton-sensing G protein-coupled receptors are
transmembrane receptors which sense acidic pH and include
GPR132 (G2A),
GPR4,
GPR68 (OGR1) and
GPR65 (TDAG8).[2] These
G protein-coupled receptors are activated when
extracellularpH falls into the range of 6.4-6.8 (typical values are above 7.0). The functional role of the low pH sensitivity of the proton-sensing G protein-coupled receptors is being studied in several tissues where cells respond to conditions of low pH including
bone and
inflamed tissues. The four known proton-sensing G protein-coupled receptors are
Class A receptors in
subfamily A15.
Nociception
Pain sensation can be initiated by
nociceptor cells that are
sensory neurons with cell bodies located in the
dorsal root ganglia. Some nociceptors respond to low pH and the pH-sensitive
amiloride-sensitive cation channel 3 has been described as a modulator of acid-induced pain sensation.[3] However, results with amiloride-sensitive cation channel 3
gene knockoutmice suggest that those channels do not fully account for acid-induced pain sensation.[4] Proton-sensing G protein-coupled receptors have been shown to be expressed in small-diameter neurons responsible for nociception where they may play a role in acid-induced pain sensation.[5] Acid-sensing neuron-mediated immediate pungent pain has been associated with
acid-sensing ion channels.[6]
Other functions
Mice lacking the Ovarian cancer G protein-coupled receptor 1 gene (OGR1) had slower
melanoma growth (KO) than control mice with OGR1 (FL), possibly due to a difference in macrophage activity.[7]
Mice lacking each of the four identified proton-sensing GPCRs have been studied.[7] Results so far suggest that these GPCRs might regulate cell proliferation (immune system cells such as
lymphocytes and
macrophages), but due to redundancy and expression of multiple proton-sensing GPCRs family members in the same cell, multiple gene knockouts are needed. Results for mice lacking OGR1 suggested a possible role for proton-sensing GPCRs in
osteoclasts.