FIGURE 4.

Model of stage 1 of saliva secretion. Secretion is initiated by activation of muscarinic receptors M₁ or M₃ by acetylcholine (ACh) or adrenergic receptors (α1) by norepinephrine (NE) and epinephrine (Epi) via specific pathways involving IP₃ release or cAMP modulation. IP₃ binds to its receptor in the ER to promote Ca²⁺ release, which is sensed by STIM1/2 in the ER membrane (EM). STIM1 recruits Orai1/TRPC to stimulate Ca²⁺ reentry into the cell. Ca²⁺ depletion from the ER recruits AQP5 to the apical membrane for water expulsion and activates NKCC1, NHE1, Ae2, Ae4, Kcnma1, and Kcnn4 in the basolateral membrane to import Na⁺ and Cl⁻ into the cellular space while exporting K⁺ and $\mathrm{HC}{\mathrm{O}}_3^{\mathrm{-}}$. In turn, ANO1 is activated in the luminal membrane to secrete Cl⁻. Na⁺ also undergoes transepithelial transport toward the lumen, resulting in NaCl-rich isotonic saliva. See glossary for abbreviations. Created with BioRender.com, with permission.