The serine proteases CAP1/Prss8 (prostasin) and CAP3/St14 (matriptase) are identified as ENaC channel-activating proteases in vitro highly suggesting that they are required for proteolytic activation of ENaC in vivo. The present study tested whether CAP3 is relevant for renal proteolytic ENaC activation and affects ENaC-mediated Na+ absorption following Na+-deprivation conditions. CAP3 knockout mice exhibit significant decrease in CAP1 protein expression with altered ENaC subunit and decreased pNCC protein abundances, but overall maintain sodium balance. RNAscope-based analyses reveal co-expression of CAP3 and CAP1 with alpha ENaC in distal tubules of the cortex from wildtype mice. Double CAP1/CAP3-deficiency maintained Na+ and K+ balance on Na+-deprived diet, restored ENaC subunit protein abundances but showed reduced NCC activity under Na+-deprivation. Overall, our data clearly show that CAP3 is not required for direct proteolytic activation of ENaC, but for its protein abundances. Our study reveal a complex regulation of ENaC by these serine proteases on the expression level rather than on its proteolytic activation.

G-protein-coupled receptors (GPCR) belong to a large family of molecules eliciting different responses to a variety of signaling molecules. These receptors participate in various physiologic pathways such as metabolism, growth, immune responses, inflammation, vision, taste, olfaction, neurotransmission and even and pathologic responses including chronic inflammatory and vascular diseases. Receptors contributing to the biological responses of renin-angiotensin system (RAS) are members of GPCR family. COVID-19-induced inflammatory cascade has been attributed to acute ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/angiotensin (1-7)/Mas axes in favor of the former. Some of the receptors contributing to activities of proteins in RAS including AT1R, AT2R and Mas receptors are members of GPCR family. It is notable that these receptors induce their effects both through G protein and β-arrestin pathway; the former exerts temporary and the latter more sustained effects. In addition to the imbalance of GPCR responses contributing to RAS activities, it has been suggested that SARS-CoV2 pathogenesis might be attributed to the activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function.This article includes a minireview about the physiological functions of GPCRs and their contribution to COVID-19.