Signal transduction desensitization

Pharmocodynamic tolerance develops in response to continued application of drugs, by mechanisms that include reversible cellular adaptation processes, such as receptor desensitization, internalization and downregu-lation as well as changes in the activity and levels of other components of the receptor s signal transduction pathways. 

Desensitization describes the rapid signal attenuation in response to stimulation of cells by receptor agonists. Changes in the coupling efficiency of receptors to signal transduction pathways and receptor internalization can account for desensitization and the development of pharmacodynamic tolerance. 

Terms in bold are defined in the signal transduction 421 enzyme cascade 422 desensitization 422... 

Ramkumar V, Stiles GL (1994) In Sibley DR, Houslay MD (eds) Regulation of cellular signal transduction pathways by desensitization and amplification. John Wiley Sons, New York, pp 217-232... 

J.B. Millar and E. Rozengurt, Heterologous desensitization of bombesin-induced mitogenesis by prolonged exposure to vasopressin a post-receptor signal transduction block, Proc. Natl. Acad. Sci. USA, 1989, 86, 3204-3208. 

These data led to the proposal of a model for desensitization based upon lateral segregation of signaling proteins in the plane of the plasma membrane. FPR in responsive cells are able to transduce a signal in the PM-L compartment that is enriched in G proteins. Activation of receptors would then allow for interaction with their signal transduction partners. In desensitized neutrophils this interaction is thought to be blocked because FPR are laterally segregated into the PM-H domain where only low levels of G protein are observed (Figure 2). 

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