Question

12. Over the years many researchers have developed treatments that affect the activity of this pathway in a way that allows individuals to get a tan without exposure to harmful UV rays. Complete the table below indicating the behaviour of melanocytes treated with each of the compounds described below in the absence of UV exposure or α-MSH. You can assume that cells being treated in these experiments have the most common (or wildtype) variant of the MC1R gene

Treatment	G protein activation (yes/no)	cAMP production (yes/no)	MITF expression (yes/no)	Eumelanin production (yes/no)
NDP-MSH - a potent analog that mimics α-MSH
db cAMP - a cyclic nucleotide derivative that mimics cAMP
Forskolin - an activator of adenylyl cyclase
Allosteric activator of TRP1

Answer 1

12. Alpha melanocyte stimulating hormone is a hormone that is induced by UV radiation. a-MSH binds to MC1R (melanocortin 1 receptor) receptor, a GPCR, is responsible for the production of eumelanin in melanocytes. Binding of a-MSH to MC1R, causes receptor dimerization and hydrolysis of Ga subunit from G protein. The Ga subunit binds to GTP and is activated. Active Ga subunit will activate adenylyl cyclase, which produces cAMP from ATP. cAMP activates protein kinase alpha, which then phosphorylates CREB that leads to activation of MITF transcription factor. The activation of downstream signaling via tyrosinase and DCT leads to eumelamin production.

Treatment	G protein activation	cAMP production	MITF expression	Eumelanin production
NDP-MSH - a potent analog that mimics α-MSH: NDP-MSH (Nle4DPhe7 alpha-MSH) will bind to MC1R as it mimics alpha-MSH	Yes The binding of NDP-MSH to the receptor will result in receptor dimerization and hydrolysis of Galpha. Galpha will bind to GTP and will be activated.	Yes Ga-GTP will activate adenylyl cyclase and activate cAMP production from ATP.	Yes Increased cAMP will activate protein kinase A which phosphorylates CREB. CREB migrates to nucleus and activate MITF transcription factor.	Yes Active MITF will activate Tyrosinase and lead to production of ICAQ form L-DOPA. This leads to production of eumelanin.
db cAMP - a cyclic nucleotide derivative that mimics cAMP	No There is no alpha-MSH or UV radiation. Hence, there is no activation of G protein as no binding to MC1R occurs.	No db cAMP is analog of cAMP. As there is no G protein activation, cAMP levels don’t rise.	Yes The db cAMP is able to activate protein kinase A and hence MITF can be activated.	Yes Active MITF will activate Tyrosinase and leads to production of eumelanin.
Forskolin - an activator of adenylyl cyclase	No Due to no binding of MC1R by alpha-MSH, there will be no activation of G protein.	Yes As there is activation of adenylyl cyclase, ATP will be broken down to cAMP.	Yes The cAMP produced will activate PKA. PKA then activated MITF via CREB phosphorylation.	Yes The MITF will activate eumelamin production via activation of eumelanin.
Allosteric activator of TRP1	No There is no binding of alpha MSH to MC1R. Hence, there is no G protein activation.	No Absence of G protein activation, will allow adenylyl cyclase to remain inactive.	No Inactive adenylyl cyclase will not cause PKA activation. Hence, MITF is not activated.	No MITF will not activate tyrosinase. Hence, L-DOPA cannot be converted to Dopaquinone. TRP1 is activated allosterically. TYR1 converts DHIC to ICAQ. ICAQ is involved in producing eumelamin. DHIC is a product of Dopachrome acted upon by DCT. Dopachrome is obtained from Dopaquinone. As no Dopaquinone or Dopachrome is produced, despite active TRP1 being present, no eumelanin will be formed.