Glossary of Pharmacology 

Constitutive activity

Constitutive activity is the activation of a receptors as well as the production of a second messenger, without the binding of an agonist. In other words, it is spontaneous activity despite the lack of an agonist.Constitutive activity was discovered upon the observation that some receptors in biological systems were activated without a ligand present.

G protein-coupled receptors (GPCRs) are a type of receptor that were found to form active states that lead to constitutive activity. This is relevant as activity can be selectively blocked by ligands. Ligands that reduced spontaneous constitutive activity are also known as inverse agonists, and those that only block agonist-induced effect, but not constitutive activity, are known as neutral antagonists.

GPCRs are the target of many drugs that are currently being used in therapeutics, and thus the knowledge of constitutive activity holds practical relevance.  

There are naturally occurring constitutively active mutations in several receptors, including GPCRs that lead to human disease (such as retinitis pigmentosa, hyperthyroidism, some autoimmune diseases, and familial male precocious puberty). Chronic constitutive activity also has associations with cancer and cell transformation. The loss of constitutive activity can also cause diseases. 

Example:

Some G-protein-coupled receptors (GPCRs) display constitutive activity that has been shown to occur in recombinant or pathologically mutated receptors. However, the physiological relevance of this process has been debated. For example, the histamine H3 receptor responsible for regulating histamine release in the brain was shown to have constitutive activity, both in vivo and in vitro. 

Teaching Tips:  

Check out this video on constitutive activity to learn more: https://youtu.be/fZeD1WoGL1U 

Linked terms:  Receptor, Ligand, Negative feedback, positive feedback, feedback loop 

Resources:  

Schwartz, J.-C., Morisset, S., Rouleau, A., Ligneau, X., Gbahou, F., Tardivel-Lacombe, J., Stark, H., Schunack, W., Ganellin, C. R., & Arrang, J. M. (2003). Therapeutic implications of constitutive activity of receptors: The example of the histamine H3 receptor. In W. W. Fleischhacker & D. J. Brooks (Eds.), Neuropsychopharmacology (pp. 1–16). Springer. https://doi.org/10.1007/978-3-7091-6020-6_1 

Krumm, B. E., Lee, S., Bhattacharya, S., Botos, I., White, C. F., Du, H., Vaidehi, N., & Grisshammer, R. (2016). Structure and dynamics of a constitutively active neurotensin receptor. Scientific Reports, 6(1), 38564. https://doi.org/10.1038/srep38564 

Kenakin, T. (2005). The physiological significance of constitutive receptor activity. Trends in Pharmacological Sciences, 26(12), 603–605. https://doi.org/10.1016/j.tips.2005.10.007 

Schwartz, J.-C., Morisset, S., Rouleau, A., Ligneau, X., Gbahou, F., Tardivel-Lacombe, J., Stark, H., Schunack, W., Ganellin, C. R., & Arrang, J. M. (2003). Therapeutic implications of constitutive activity of receptors: The example of the histamine H3 receptor. In W. W. Fleischhacker & D. J. Brooks (Eds.), Neuropsychopharmacology (pp. 1–16). Springer. https://doi.org/10.1007/978-3-7091-6020-6_1 

Tao, Y.-X. (2008). Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics. Pharmacology & Therapeutics, 120(2), 129–148. https://doi.org/10.1016/j.pharmthera.2008.07.005 

Kenakin, T. (2005). The physiological significance of constitutive receptor activity. Trends in Pharmacological Sciences, 26(12), 603–605. https://doi.org/10.1016/j.tips.2005.10.007 

Schwartz, J.-C., Morisset, S., Rouleau, A., Ligneau, X., Gbahou, F., Tardivel-Lacombe, J., Stark, H., Schunack, W., Ganellin, C. R., & Arrang, J. M. (2003). Therapeutic implications of constitutive activity of receptors: The example of the histamine H3 receptor. In W. W. Fleischhacker & D. J. Brooks (Eds.), Neuropsychopharmacology (pp. 1–16). Springer. https://doi.org/10.1007/978-3-7091-6020-6_1 

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