Question

Briefly predict the major consequences of each of the following mutations affecting glycogen utilization. (a) Loss of GTPase activity of the G-protein \(\alpha\) subunit. (b) Loss of phosphodiesterase activity.

Short answer

(a) Continuous glycogen breakdown due to prolonged signal activation. (b) Persistent high cAMP levels, leading to sustained glycogen breakdown.

Step-by-step solution

Understanding GTPase Activity in G-proteins

GTPase activity in the G-protein \( \alpha \) subunit is crucial for terminating the signal transduction pathway. Normally, the \( \alpha \) subunit hydrolyzes GTP to GDP, thereby inactivating itself and stopping further signal propagation. This process ensures that the signal does not remain indefinitely active.

Assessing Consequences of Loss of GTPase Activity

If the G-protein \( \alpha \) subunit loses its GTPase activity, it will remain in its active GTP-bound state. This prolonged activation can continuously stimulate adenylyl cyclase, leading to elevated cAMP levels and persistent activation of protein kinase A (PKA), causing increased glycogen breakdown and glucose release.

Understanding Phosphodiesterase Activity

Phosphodiesterase is responsible for converting cAMP into AMP, which helps in reducing the levels of cAMP in the cell. This reduction is vital for turning off PKA signaling and associated pathways, gradually returning the cell to its basal state.

Assessing Consequences of Loss of Phosphodiesterase Activity

If phosphodiesterase activity is lost, cAMP levels remain high because it cannot be degraded. This leads to continuous activation of PKA, resulting in sustained glycogen breakdown and glucose release due to prolonged glycogen phosphorylase activation and glycogen synthase inhibition.

Key concepts

GTPase activity

GTPase activity plays a crucial role in cellular signaling, particularly in the function of G-proteins. GTPases act like a switch that can turn on or off signaling pathways. This activity is mainly seen in the G-protein \( \alpha \) subunit, where it converts bound GTP to GDP. This conversion is important because it inactivates the \( \alpha \) subunit, halting further signal transmission.

When the GTPase activity is lost, this regulatory mechanism fails. Instead of being inactivated, the \( \alpha \) subunit remains active, continuously engaged in signal transduction processes. This can lead to persistent activation of downstream enzymes like adenylyl cyclase, resulting in prolonged cellular responses such as increased glucose production from glycogen stores.

G-protein

G-proteins are molecular switches that transmit signals from outside the cell to its interior. They play a key role in converting extracellular signals into intracellular actions. These proteins are made up of \( \alpha \), \( \beta \), and \( \gamma \) subunits.

• When a receptor is activated by a signal such as a hormone, the G-protein undergoes a conformational change.
• This causes the \( \alpha \) subunit to exchange GDP for GTP, becoming active.
• The active \( \alpha \) subunit then detaches and interacts with other enzymes within the cell, such as adenylyl cyclase, to propagate the signal.

Without proper regulation, G-proteins can lead to excessive signal transduction, affecting processes like glycogen metabolism as seen in the persistent activation due to lost GTPase activity.

cAMP

Cyclic adenosine monophosphate (cAMP) serves as a secondary messenger in many biological processes. It amplifies the signal from the cell surface to its interior. This molecule is produced from ATP by the enzyme adenylyl cyclase, usually activated by G-proteins.

cAMP plays a pivotal role in regulating glycogen breakdown. It activates protein kinase A (PKA), which then phosphorylates various target proteins to facilitate further cellular reactions, including the conversion of glycogen to glucose. When phosphodiesterase activity is absent, cAMP levels remain elevated, thereby sustaining high activity of PKA and leading to continuous glycogenolysis.

signal transduction

Signal transduction involves a series of molecular events whereby a cell interprets and responds to signals from its environment. This complex process allows cells to react to external stimuli with appropriate responses. Initially, a signaling molecule binds to a receptor on the cell surface, initiating the cascade.

In the context of G-protein-coupled pathways, this binding activates the G-protein, which in turn stimulates enzymes like adenylyl cyclase. This activation leads to the production of secondary messengers like cAMP. Each step involves specific proteins, each amplifying the signal to elicit significant cellular responses. Therefore, the components of signal transduction, including G-proteins and cAMP, are key in intricate pathways such as glycogen metabolism regulation.

protein kinase A

Protein kinase A (PKA) is an important enzyme that becomes active in the presence of increased cAMP levels. Its primary role is to phosphorylate other proteins, which can either activate or inhibit their function. In glycogen metabolism, PKA activation leads to a cascade of events, essential for the mobilization of glucose stores.

When cAMP is present in high levels due to either continuous G-protein activation or lack of phosphodiesterase activity, PKA remains persistently active. This ongoing action further promotes glycogen breakdown, elevating glucose availability in cells. PKA acts as a major control mechanism translating cAMP signals into actionable cellular outcomes.