Question

How does elevation of cyclic AMP in eukaryotic cells lead to altered transcription of certain genes?

Short answer

Answer: The steps involved in the process are: 1) Increase in cAMP levels, 2) Activation of protein kinase A (PKA), 3) Phosphorylation of target proteins by PKA, 4) Regulation of gene transcription, and 5) Cellular response to altered gene transcription.

Step-by-step solution

Increase in cAMP levels

When a specific extracellular signal, such as a hormone or a neurotransmitter, binds to a G-protein coupled receptor (GPCR) on the cell surface, it activates the enzyme adenylate cyclase. This enzyme, in turn, catalyzes the conversion of adenosine triphosphate (ATP) to cAMP, leading to an increase in intracellular cAMP levels.

Activation of protein kinase A (PKA)

Elevated cAMP levels lead to the activation of protein kinase A (PKA), a ubiquitously expressed serine/threonine kinase. In its inactive form, PKA is a holoenzyme composed of two regulatory subunits (R) and two catalytic subunits (C). The increase in cAMP levels results in binding of cAMP to the regulatory subunits, causing a conformational change that releases the active catalytic subunits.

Phosphorylation of target proteins by PKA

Once activated, the catalytic subunits of PKA can phosphorylate specific target proteins, including other kinases and transcription factors, at serine or threonine residues. This phosphorylation event can either activate or inhibit the function of the target proteins, depending on their specific role in cellular processes.

Regulation of gene transcription

One of the primary targets of PKA is the transcription factor called cAMP response element-binding protein (CREB). When phosphorylated by PKA, CREB becomes active and can bind to cAMP response elements (CRE) within the promoter regions of certain genes. This binding recruits additional coactivator proteins, such as CREB-binding protein (CBP) and p300, forming a transcription initiation complex that leads to the increased transcription of target genes.

Cellular response to altered gene transcription

The change in transcription levels of specific genes can lead to various cellular responses, depending on the identity of the affected genes. These responses may include alterations in cell division, differentiation, metabolism, or other essential processes critical for the overall function of the organism. In summary, the elevation of cAMP levels in eukaryotic cells leads to the activation of PKA, which in turn phosphorylates and activates target proteins, including the transcription factor CREB. This activation results in altered transcription of specific genes, leading to various cellular responses depending on the target genes affected.

Key concepts

G-protein Coupled Receptors

G-protein coupled receptors (GPCRs) are a large family of cell surface receptors that play a pivotal role in cellular communication and signal transduction. These receptors detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses. The binding of a ligand, such as a hormone or neurotransmitter, to the GPCR induces a conformational change in the receptor, which then activates an associated G-protein by promoting the exchange of GDP for GTP on the G-protein's alpha subunit. The G-protein disassociates into alpha and beta-gamma subunits, which can then activate or inhibit various downstream effectors, such as enzymes and ion channels.

One key effector activated by G-proteins is the enzyme adenylate cyclase, which catalyzes the conversion of ATP to cyclic AMP (cAMP), serving as a crucial step in the cAMP signaling pathway. This process is a classic example of how extracellular signals can lead to a cascade of intracellular events that ultimately modulate cellular functions and gene expression.

Protein Kinase A (PKA)

Protein kinase A, also known as PKA or cAMP-dependent protein kinase, is a crucial component of the cAMP signaling pathway. It is involved in the phosphorylation of various proteins, including enzymes, receptor, and transcription factors, which can lead to changes in their activity. In its inactive state, PKA exists as a tetrameric holoenzyme with two regulatory and two catalytic subunits. The binding of cAMP to the regulatory subunits induces a structural change that releases the active catalytic subunits. These subunits can then transfer a phosphate group from ATP to specific serine or threonine residues on target proteins. The phosphorylation of these targets can have diverse cellular effects, such as modifying enzyme activities, opening ion channels, or changing patterns of gene expression.

A notable aspect of PKA's function is its specificity; the kinase is able to selectively phosphorylate certain proteins while leaving others unmodified. This specificity is accomplished through the association of PKA with various scaffold proteins that target the kinase to specific subcellular locations, allowing for precise regulation of cellular processes.

cAMP Response Element-Binding Protein (CREB)

The cAMP response element-binding protein (CREB) is a cellular transcription factor that is activated by PKA as part of the cAMP signaling pathway. When CREB is phosphorylated on a specific serine residue by the active catalytic subunits of PKA, it undergoes a conformational change that allows it to bind to DNA sequences known as cAMP response elements (CREs). These CREs are found in the promoter regions of genes regulated by cAMP.

Upon phospho-CREB binding, the transcription of these genes is altered. This modification often involves the recruitment of coactivator proteins, which can include other transcription factors and histone acetyltransferases like CREB-binding protein (CBP) and p300. This recruitment leads to changes in chromatin structure, making the DNA more accessible to the transcriptional machinery and enabling the initiation of gene transcription. The activity of CREB and its role in transcription is a critical aspect of the cellular response to various extracellular signals, influencing processes such as memory formation, metabolism, and cellular proliferation.

Gene Transcription Regulation

Gene transcription regulation is the process by which a cell controls the transcription of specific genes to mRNA, which is the first step in gene expression. It involves a complex network of signals, activators, repressors, and various transcription factors, like CREB, operating in concert to ensure genes are turned on or off at the right time and in the right cells.

Within the cell nucleus, transcription factors bind to regulatory DNA sequences, such as enhancers, silencers, and promoters, to either stimulate or inhibit the recruitment of RNA polymerase, the enzyme responsible for synthesizing mRNA from DNA. The regulation of gene transcription is influenced by extracellular signals that can result in the post-translational modification of transcription factors, alterations in chromatin structure, and changes in the localization and interaction of transcriptional machinery components.

This dynamic interplay is essential for cells to adapt to their internal and external environments, allowing them to respond to stimuli in a precise and coordinated manner. Dysregulation of gene transcription can lead to a variety of diseases, underscoring the importance of tight control over this fundamental biological process.