Sensitization of adenylate cyclase is a recently discovered phenomenon. Melatonin can induce a sensitized response of adenylate cyclase in ovine pars tuberalis cells where the receptor for melatonin is endogenously expressed. Although the mechanism is not fully understood, sensitization of adenylate cyclase may be an important part of the mechanism by which melatonin encodes daylength in the pars tuberalis of sheep and other animals. We used this as a hypothesis to search for a natural ligand that would activate adenylate cyclase in ovine pars tuberalis cells. The approach revealed pituitary adenylate cyclase activating polypeptide to be an indirect activator of adenylate cyclase in the ovine pars tuberalis. We discuss this in relation to the mechanism and importance of sensitization to the function to the pars tuberalis.