Figure 8. Summary diagram of the proposed adrenomedullin (ADM) signaling pathway in the retina. Protein kinase C (PKC) activation can lead to increased transcription of the ADM gene via a PKC enhancer element. The ADM precursor preproadrenomedullin is cleaved to proadrenomedullin, which is then cleaved into the secreted peptide ADM and the proadrenomedullin NH₂-terminal peptide (PAMP). ADM is secreted and binds to the G-protein coupled receptor calcitonin receptor like receptor (CRLR) that is associated with either the receptor activity modifying protein RAMP2 or RAMP3 to activate a signaling cascade that increases cyclic adenosine monophosphate (cAMP) by activating adenylyl cyclase. Increases in cAMP levels activate protein kinase A (PKA), which increases calcium levels by opening membrane calcium channels or by releasing intracellular calcium stores. The overall increase in intracellular calcium can increase nitric oxide (NO) production by directly stimulating nNOS or by activating nNOS through the activation of the calcium-activated phosphatase, calcineurin (CaN), which dephosphorylates nNOS at an inhibitory phosphorylation site at serine⁸⁴⁷. Increases in NO production can then increase in cGMP synthesis by activating soluble guanylyl cyclase (sGC).