Question

Any change in the amino acid sequence of TAS2R38 has the potential to interfere with this signal diagrammed above. the amino acid difference at position 49, which alters a proline to an alanine, is in the part of GPCR protein that is located on the intracellular side of the membrane. what step in cell signaling could changing the amino aside at position 49 interrupt?

Answer 1

The TAS2R38 gene codes for the T2R receptor involved in bitter taste sensing. This receptor, present in the taste buds, binds to the bitter compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil. It is a G protein coupled receptor that is made up of an extracellular domain, a 7 membered transmembrane domain and an intracellular domain. When the ligand binds to the extracellular domain of receptor, there is a conformational change in the transmembrane domain. As a result, GDP in Ggust-alpha subunit of G protein is exchanged for GTP by GEF (guanine exchange factor). Gagust-GTP then dissociates form the Gagustbg G protein and will bind and inactivate to adenylyl cyclase associated with receptor in plasma membrane. Thus, Adenylyl cyclase cannot break down ATP to cAMP, thereby inhibiting its signaling. The Gbg subunit will then activate phospholipase C which acts on PIP2 to form IP3 and DAG. IP3 causes mobilization of calcium into cytoplasm from ER via calcium channels. Calcium activates TRPM5 channels in the cell membrane, which are cation channels, allowing flow of sodium ions. It also activates CALHM1 for release of ATP that stimulates the neurons via purinergic receptors.

The amino acid alanine is present in first intracellular domain of the receptor. The intracellular domain is bound to the G proteins. Hence, alanine (PAV) to proline change (seen in AVI) will affect the dissociation of G alpha subunit from the G protein. Thus, signaling is inhibited and no taste reception occurs as the neurons are not stimulated. Hence, AVI are non-tasters.