Phospho-CREB protein, shown in Figure 3.10, increases the transcriptional response mediated by cAMP and PKA. These effects can be extremely rapid, such as the adrenaline response, as they target existing proteins. Consequently, cAMP can produce various cellular effects, both direct and indirect, mediated by PKA, including effects in the cytoplasm and nucleus of cells.

Cholera toxin, secreted by Vibrio cholera, inhibits the GTPase activity of the G-protein αs subunit through ADP ribosylation. This keeps αs in its activated state, leading to the activation of adenylyl cyclase and an increase in cAMP/PKA levels. In the intestines, elevated levels of PKA enhance cystic fibrosis transmembrane conductance regulator (CFTR)–mediated chloride secretion. This results in secretory diarrhea and extensive fluid loss, which are characteristic symptoms of cholera. Similarly, the bacterium Bordetella pertussis, responsible for whooping cough, secretes pertussis toxin, which ADP ribosylates the αi subunit. This ribosylation inactivates αi, reducing the inhibition of adenylyl cyclase and leading to increased levels of cAMP/PKA.

Heterotrimeric G proteins also play a role in phototransduction. In rod cells of the eye, absorption of light by rhodopsin activates the G protein transducin, specifically the αt subunit. This activation, in turn, activates cGMP phosphodiesterase. The phosphodiesterase lowers the concentration of cGMP, leading to the closure of a cGMP-activated cation channel. This alteration in cation channel activity affects the membrane voltage. The high sensitivity of rods to light is due to the abundance of rhodopsin and the signal amplification provided by the G protein–cGMP phosphodiesterase–cGMP channel signaling pathway.

In addition to phototransduction, heterotrimeric G proteins also regulate phospholipases. Ligands that activate receptors coupled to the αq subunit stimulate phospholipase C, which converts phosphatidylinositol 4,5-biphosphate to inositol 1,4,5-triphosphate (InsP3) and diacylglycerol. InsP3 serves as a second messenger that diffuses to the endoplasmic reticulum, activating a ligand-activated Ca++ channel and releasing Ca++ into the cytosol. On the other hand, diacylglycerol activates protein kinase C, which phosphorylates effector proteins. Both Ca++ and protein kinase C influence effector proteins and other signaling pathways to elicit responses.
Fig. 3.10 ). Phospho-CREB protein increases the transcripresponse mediated by cAMP and PKA. Because these effects tion of many genes, which can in turn produce a distinct set target existing proteins, they can be extremely rapid (e.g., of responses with much slower kinetics. Hence, cAMP has adrenaline response). In addition to cytoplasmic signaling, many cellular effects, including direct and indirect effects the catalytic subunit of PKA can enter the nucleus of cells mediated by PKA.
CHAPTER 3 Signal Transduction, Membrane Receptors, Second Messengers, and Regulation of Gene Expression
Cholera toxin, secreted by Vibrio cholera, catalyzes the ADP ribosylation of the G-protein αs subunit, which inhibits the GTPase activity of αs. Thus αs remains in its activated, GTP-bound state, which in turn causes activation of adenylyl cyclase and an increase in cAMP/PKA levels. In the intestines, elevated levels of PKA increase cystic fibrosis transmembrane conductance regulator (CFTR)–mediated chloride secretion, which leads to secretory diarrhea and extensive loss of fluids, characteristic of cholera. Bordetella pertussis, the bacterium that causes whooping cough, secretes pertussis toxin, which ADP ribosylates the αi subunit. In this case, the ribosylation inactivates αi, reducing the inhibition of adenylyl cyclase and thus also leading to increased levels of cAMP/PKA.
Heterotrimeric G proteins also regulate phototransduction. In rod cells in the eye, absorption of light by rhodopsin activates the G protein transducin, which via the αt subunit activates cGMP phosphodiesterase. Activation of this phosphodiesterase lowers the concentration of cGMP and thereby closes a cGMP-activated cation channel. The ensuing change in cation channel activity alters the membrane voltage. The exquisite sensitivity of rods to light—rods can detect a single photon of light—is due to the abundance of rhodopsin in rods and amplification of the signal (a photon of light) by the G protein–cGMP phosphodiesterase–cGMP channel signaling pathway (see for more details).
Heterotrimeric G proteins also regulate phospholipases, a family of enzymes that modulate a variety of signaling pathways. Ligands that activate receptors that are coupled to the αq subunit stimulate phospholipase C, an enzyme that converts phosphatidylinositol 4,5-biphosphate to inositol 1,4,5-triphosphate (InsP3) and diacylglycerol. InsP3 is a second messenger that diffuses to the endoplasmic reticulum, where it activates a ligand-activated Ca++ channel to release Ca++ into the cytosol, whereas diacylglycerol activates protein kinase C, which phosphorylates effector proteins. As noted earlier, both Ca++ and protein kinase C influence effector proteins, as well as other signaling pathways, to elicit responses.