Inhibition Of Soluble Adenylyl Cyclase (Sac) Rescues Defective Melanosomal Ph And Pigmentation In Oculocutaneous Albinism Type 2 (Oca2)

Oculocutaneous albinism type 2 (OCA2) results from a defective melanosomal anion channel leading to an acidic melanosomal pH, reduced tyrosinase activity and decreased melanin production. Reduced melanin production in OCA2 affected people leads to the development of skin cancers and other forms of damage due to ultraviolet radiation. Currently, pharmacological approaches to repair melanosomal pH and pigmentation do not exist. We have shown that inhibition of soluble adenylyl cyclase (sAC) in melanocytes alkalinizes melanosomal pH and enhances tyrosinase (TYR) activity. Therefore, we asked whether inhibition of sAC would restore wild type melanosomal pH and melanin production in OCA2 melanocytes and mice. OCA2 melanocytes had a more acidic melanosomal pH and sAC inhibitors restored wild type melanosomal pH and increased tyrosinase activity. We generated Oca2-/-, sAC floxed (f/f), Tyr-CRE-ERT2 mice and induced sAC knock out via post-natal (P2-4), topical application of 4-hydroxytamoxifen. The Oca2-/-; sAC-/- mice (n=23) had noticeably darker hair color at P28 as compared to OCA2-/-; sACf/f (n=14) littermates. HPLC analysis of the hair collected on P28 showed a significant increase in total melanin in Oca2-/-; sAC-/- mice corresponding to increased amounts of both eumelanin (PTCA) and pheomelanin (AHP). Individual hair strands of Oca2-/-; sAC -/- mice revealed distinctive banding patterns as compared to Oca2-/-; sACf/f littermates, and histology showed that the Oca2-/-; sAC -/- mice also had less overall hair follicles. Thus, loss of sAC in melanocytes may affect hair morphogenesis. In conclusion, our studies show that restoring melanosomal pH by inhibiting the sAC signaling pathway is a potential therapeutic approach for the treatment of OCA2 and related diseases.