Glucagon and the glucagon receptor are a primary source of control over blood glucose concentrations and are especially important to studies of diabetes in which the loss of control over blood glucose concentrations clinically defines the disease. A complementary DNA clone for the glucagon receptor was isolated by an expression cloning strategy, and the receptor protein was expressed in several kidney cell lines. The cloned receptor bound glucagon and caused an increase in the intracellular concentration of adenosine 3', 5'-monophosphate (cAMP). The cloned glucagon receptor also transduced a signal that led to an increased concentration of intracellular calcium. The glucagon receptor is similar to the calcitonin and parathyroid hormone receptors. It can transduce signals leading to the accumulation of two different second messengers, cAMP and calcium.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

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Reporter, proliferation, and direct STAT activation assays using cell lines expressing transfected receptors revealed differences between the receptor complexes. IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation. These results demonstrate that, although this subclass exhibits receptor complex redundancy, there are differences in ligand/receptor interactions and in signal transduction that may lead to specificity and a distinct biology for each cytokine.