Activation of Gene Transcription by G Protein Coupled Receptors

As mentioned early in this chapter, intracellular signal-transduction pathways can have short-term and long-term effects on the cell. Short-term effects (seconds to minutes) result from modulation of the activity of preexisting enzymes or other proteins, leading to changes in cell metabolism or function. Most of the pathways activated by G proteincoupled receptors fall into this category. However, GPCR signaling pathways also can have long-term effects (hours to days) owing to activation or repression of gene transcription, leading in some cases to cell proliferation or to differentiation into a different type of cell. Earlier we discussed how a signal-induced rise in cytosolic Ca2+ can lead to activation of transcription factors. Here we consider other mechanisms by which some G protein-coupled receptors regulate gene expression.

Membrane-Localized Tubby Transcription Factor Is Released by Activation of Phospholipase C

The tubby gene, which is expressed primarily in certain areas of the brain involved in control of eating behavior, first attracted attention because of its involvement in obesity. Mice bearing mutations in the tubby gene develop adult-onset obesity, and certain aspects of their metabolism resemble that of obese humans.

Sequencing of the cloned tubby gene suggested that its encoded protein contains both a DNA-binding domain and a transcription-activation domain (Chapter 11). However, the Tubby protein was found to be localized near the plasma membrane, making it an unlikely candidate as a transcription factor. Subsequent studies revealed that Tubby binds tightly to PIP2, anchoring the protein to the plasma membrane (Figure 13-31). Hormone binding to Go- or Gq-coupled receptors, which activate phospholipase C, leads to hydrolysis of PIP2 and release of Tubby into the cytosol. Tubby then enters the nucleus and activates transcription of a still unknown gene or genes. Identification of these genes should provide clues about how their encoded proteins relate to obesity. I

Phospholipase C

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