Intracellular Signaling and Cellular Responses

Intracellular Signalling

• Cells signal to each other in various ways
• A "second messenger" is a molecule that relays a signal from a cell membrane receptor to the inside of a cell, initiating a response
• Transmembrane receptors and their associated signaling pathways are crucial for controlling gene activity
• G proteins, cAMP, phospholipase C, diacylglycerol (DAG), inositol triphosphate (IP3), and Receptor Tyrosine Kinase (RTK) play vital roles in signal transduction pathways
• Metabolic processes can be regulated through intracellular signaling
• Signal pathways can overlap, and intracellular signaling is vital for drug action

Cellular Responses

• Cells change metabolic activities. For instance, glucagon can cause liver cells to switch from glycogen synthesis to glycogen breakdown
• Binding of an antigen to a mast cell triggers histamine release
• Changes in gene expression. Examples include epidermal growth factor (EGF) initiating cell growth and light activation of rhodopsin
• Extracellular signals that drive these responses can include amino acids and their derivatives, steroids, prostaglandins, proteins and peptides, and gases

Different Ways for Cells to Signal

• Endocrine: Signals produced in one part of the body travel through the bloodstream to target cells elsewhere
• Autocrine: Signals act on the same cell that produces them
• Paracrine: Signals act on neighboring cells
• Contact dependent: Signals involve direct interaction between cells
• Neuronal: Electrical signals transmitted along neurons, with messages passed to other cells via synapses

Receptor/Signal

• Cells must have specific receptors to respond to signals
• Receptors are highly selective and have high affinity for their target signals
• Signals can bind to various receptor types
• Signals are eventually deactivated

Location of Receptor

• Cell surface receptor: Hydrophilic signals (such as adrenaline) bind to receptors on the cell surface, triggering intracellular responses
• Intracellular receptor: Hydrophobic signals (like steroid hormones) cross the cell membrane and bind to intracellular receptors, initiating responses within the cell

Types of Signaling

• Signals can bind to receptors, causing membrane depolarization (e.g., acetylcholine) or direct activation of transcription factors (e.g., steroids)
• Signals can trigger the generation of secondary messengers like cAMP (e.g., glucagon) to activate kinase cascades (e.g., EGF)

Ion-Channel Coupled Receptors

• Ion channel-coupled receptors respond to signals through ion flow (e.g., acetylcholine binding to nicotinic acetylcholine receptors) causing membrane depolarization

Direct Activation of Transcription Factors

• Steroid hormones have hormone binding domains, DNA binding domains, and domains for interaction with other transcription factors
• Binding induces conformational changes allowing DNA binding and activation of transcription
• These are ligand-dependent transcription factors

Secondary Messengers

• Signal molecules are first messengers. Secondary messengers can include cyclic AMP (cAMP), cyclic GMP, IP3/DAG, and Calcium
• Second messengers are triggered by enzymes and generate intracellular responses

G-protein-Coupled Receptor (GPCR)

• GPCRs are integral membrane proteins linked to G proteins.
• Adrenaline is an example, activating adenylyl cyclase (adenylate cyclase) which creates cAMP.
• The activation of phospholipase C leads to the formation of IP3 and DAG

Guanine Nucleotide Binding Proteins (G-proteins)

• G-proteins are heterotrimeric complexes with alpha, beta, and gamma subunits
• They exist in an inactive state bound to GDP and an active state bound to GTP.
• G-protein activation involves dissociation of the alpha subunit, which then activates effector enzymes

GPCR Signaling to Effector Enzymes

• A signal molecule binds to the receptor triggering a response in the target cell
• The G protein dissociates and activates an effector enzyme
• The effector enzyme produces a second messenger
• The G protein complex re-associates and the signaling ends

cAMP Dependent Protein Kinase A (PKA)

• PKA is a tetrameric enzyme with regulatory and catalytic subunits
• cAMP binding to regulatory subunits causes dissociation and activation of catalytic subunits. This is important for metabolic regulation.
• A kinase cascade is typical, amplifying the signal

cAMP Mediated Effects on Glycogen Breakdown

• Hormones like glucagon activate a cascade, causing glycogen breakdown, while glycogen synthesis is inhibited

Signal Amplification

• Kinase cascades amplify hormonal signaling by increasing at each step in the cascade

cAMP

• cAMP is formed via adenylyl cyclase, and deactivated by phosphodiesterase

cAMP and Gene Transcription

• PKA phosphorylates the CREB (cAMP response element binding protein), activating the transcription of specific genes, important for long-term responses

GPCR and IP3/DAG

• Some GPCR activate phospholipase C and generate IP3 and DAG, raising intracellular Ca2+ and activating protein kinase C

Receptor Activation of Phospholipase C

• Signal molecules activate GPCR’s triggering a signaling cascade culminating in activation of protein kinase C. IP3 and DAG are involved.

Direct Activation of Enzymatic Kinase Cascade

• Ligands like EGF cause autophosphorylation of receptor tyrosine kinase (RTK) domains.
• Adaptor proteins like Grb2 bind to receptor, leading to GDP/GTP exchange on Ras, which drives kinase cascades that activate transcription factors

Ras as a G-protein

• Ras is a monomeric G-protein
• GTP-Ras triggers a kinase cascade, including MAPK, in response to growth signals

Overlap

• Hormones can trigger different receptors or different pathways, leading to common effects
• Different signals can converge on the same intracellular pathway
• "Cross-talk" occurs when pathways block or influence one another

Summary

• Extracellular signals activate receptors, which then trigger responses within the target cell, including via cAMP pathways, IP3/DAG pathways, or direct kinase cascade activation. Ligand-receptor activation can also influence gene transcription.

This quiz explores the intricate mechanisms of intracellular signaling and how cells respond to various external stimuli. Topics include second messengers, transmembrane receptors, and the roles of G proteins and related molecules in signal transduction. Understanding these processes is crucial for grasping metabolic regulation and drug action.