The Pathogenesis of Cholera
Cholera is a digestive disease characterized by severe diarrhea. It is caused by infection with the Vibrio cholerae bacterium (gram-negative), which releases the cholera toxin (CT) to exert its effects. CT is endocytosed by intestinal cells, and manipulates the local G protein-coupled receptor (GPCR) apparatus to exert its effects.
GPCR. The alpha subunit of the trimeric G protein dissociates upon GDP phosphorylation into GTP. In a Gs signaling pathway (as is relevant for cholera), the G-alpha/GTP complex activates adenylyl cyclase (via using the 3rd phosphate of GTP to phosphorylate AC) to begin the signal transduction cascade. The remaining G-beta/G-gamma subunit can also participate in signal transmission by, for example, opening an ion channel.
CT causes post-translational modification of the G protein’s GTPase such that adenylyl cyclase is now constitutively active. Thus, ATP is converted to cAMP at a high rate. This second messenger increases the activity of protein kinase A, which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Upon opening of this protein channel, Cl- ions rush out into the intestinal lumen. This causes a concentration imbalance of Cl-, so the HCO3-/Cl- exchanger is activated. To counteract the release of Cl- into the lumen, HCO3- is released into the lumen as well, and some Cl- is taken back up into cells (but not enough to fully negate the effects of the leaky CFTR). K+ is transported into the intestinal lumen to balance the negative charge. All these osmotically active ions in the intestines bring water into the lumen as well, resulting in severe diarrhea. Cholera also causes metabolic acidosis, due to HCO3- loss from cells. This results in rapid hyperventilation to rid the blood of CO2 and restore pH balance.
Carriers of cystic fibrosis (CF) typically have less severe cholera, due to partial CFTR channel blockage. In addition, due to the low expressivity of the heterozygote condition, carriers do not have major CF symptoms, either.
Brief explanation of expressivity and related genetics terms.
Here are some sources that helped me understand this:
https://www.youtube.com/watch?v=N7o0Fkz9iGE - a short summary of GPCR function and types throughout the body.
https://www.nature.com/scitable/topicpage/gpcr-14047471/ - more about GPCRs!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089049/ - a paper about the cholera toxin.
