Biosignaling 2: Videos & Practice Problems

cAMP (cyclic adenosine monophosphate) acts as a secondary messenger in cellular signaling pathways. It is generated by the enzyme adenylyl cyclase in response to extracellular signals like hormones and neurotransmitters. cAMP activates protein kinase A (PKA) by binding to its regulatory subunit, causing the release of the catalytic subunit. This activation allows PKA to phosphorylate serine or threonine residues on various target proteins, leading to a phosphorylation cascade. This cascade amplifies the initial signal, resulting in significant cellular responses such as the release of glucose from glycogen stores. Additionally, cAMP levels are tightly regulated by cyclic nucleotide phosphodiesterase, which breaks down cAMP into AMP, ensuring proper control of signaling pathways.

Protein kinase A (PKA) is activated by the secondary messenger cAMP (cyclic adenosine monophosphate). PKA is composed of two regulatory subunits and two catalytic subunits. In its inactive form, the regulatory subunits bind to the catalytic subunits, inhibiting their activity. When cAMP levels increase, cAMP molecules bind to the regulatory subunits, causing a conformational change that releases the catalytic subunits. These free catalytic subunits are now active and can phosphorylate serine or threonine residues on target proteins, initiating a phosphorylation cascade that leads to various cellular responses.

A phosphorylation cascade is a series of events where one enzyme phosphorylates another, leading to a chain reaction of phosphorylation events. This cascade amplifies the initial signal, resulting in a significant cellular response. For example, in the epinephrine signaling pathway, epinephrine binds to a G protein-coupled receptor, activating adenylyl cyclase, which increases cAMP levels. cAMP activates protein kinase A (PKA), which then phosphorylates phosphorylase b kinase, converting it to its active form. This active kinase then phosphorylates glycogen phosphorylase, leading to the breakdown of glycogen into glucose-1-phosphate, which is eventually released as glucose into the blood. This cascade ensures a rapid and amplified response to the initial signal.

Cholera toxin disrupts cellular signaling pathways by modifying the G protein involved in the cAMP pathway. The toxin catalyzes the ADP-ribosylation of the G protein, locking it in its active form. This leads to continuous activation of adenylyl cyclase, resulting in excessive production of cAMP. Elevated cAMP levels cause the overactivation of protein kinase A (PKA), which in turn leads to the excessive secretion of chloride and sodium ions into the intestinal lumen. Water follows these ions osmotically, resulting in severe watery diarrhea. The primary concern for cholera patients is dehydration due to the massive loss of fluids, which can be life-threatening if not treated promptly.

Adaptation in signal transduction pathways involves mechanisms that reduce the sensitivity of the pathway to continuous stimulation. One such mechanism is receptor phosphorylation by specific kinases, such as beta-adrenergic receptor kinase (βARK) in the epinephrine pathway. βARK phosphorylates the receptor, leading to the binding of beta-arrestin. Beta-arrestin facilitates the internalization of the receptor into endosomes, reducing the number of receptors available on the cell surface. This decreases the cell's responsiveness to the signal. Additionally, the internalized receptors can be either degraded or recycled back to the cell surface, allowing the cell to modulate its sensitivity to the signal over time.