2.3 Receptors and signal transduction

Receptors and signal transduction are crucial for cellular communication in the nervous system. They allow neurons to respond to neurotransmitters and other chemical signals, triggering complex intracellular processes that shape neuronal function and behavior.

Understanding these mechanisms is key to grasping how the brain processes information. From fast-acting ligand-gated ion channels to slower G protein-coupled receptors, these molecular machines form the basis of neural signaling and plasticity.

Ligand-gated vs G protein-coupled receptors

Structure and function of ligand-gated ion channels

• Ligand-gated ion channels are transmembrane proteins that open or close in response to the binding of a specific neurotransmitter or drug (acetylcholine, GABA, glycine), allowing ions to flow through the channel and change the cell's membrane potential
• Consist of multiple subunits that form a central pore, with binding sites for neurotransmitters or other ligands on the extracellular domain
• When a ligand binds to the receptor, it induces a conformational change that opens the ion channel, allowing ions (Na+, K+, Ca2+, Cl-) to flow through and alter the cell's electrical activity
• Play a crucial role in fast synaptic transmission, as they can rapidly change the postsynaptic cell's membrane potential in response to neurotransmitter release

Structure and function of G protein-coupled receptors (GPCRs)

• GPCRs are transmembrane proteins that activate intracellular signaling cascades through the activation of G proteins upon binding to a specific neurotransmitter or hormone (dopamine, serotonin, epinephrine)
• Have seven transmembrane domains, with an extracellular ligand-binding site and an intracellular domain that interacts with G proteins
• The binding of a ligand causes a conformational change in the receptor, leading to the activation of the associated G protein (Gs, Gi, Gq) and the initiation of intracellular signaling cascades
• GPCRs are involved in slower, modulatory synaptic transmission and the regulation of various cellular processes, such as metabolism, gene expression, and cell survival

Signal transduction in cellular communication

Process of signal transduction

• Signal transduction is the process by which extracellular signals, such as neurotransmitters or hormones, are converted into intracellular responses through a series of biochemical reactions
• Allows cells to respond to their environment and communicate with each other, enabling the coordination of cellular activities and the maintenance of homeostasis
• Involves the binding of a ligand to a receptor, which triggers a conformational change in the receptor and the activation of intracellular signaling molecules
• Signaling cascades amplify the initial signal, allowing a small number of activated receptors to generate a large intracellular response

Regulation of signal transduction pathways

• Signal transduction pathways can be regulated at multiple levels to fine-tune cellular responses and prevent excessive or prolonged activation
• Receptor desensitization occurs when prolonged exposure to a ligand leads to a decrease in the receptor's responsiveness, often through phosphorylation or internalization of the receptor
• Feedback inhibition involves the activation of inhibitory signaling molecules by the pathway itself, which can dampen or terminate the signaling cascade
• Cross-talk between different signaling pathways allows for the integration of multiple signals and the modulation of cellular responses based on the overall cellular context

Intracellular signaling pathways of neurotransmitters

Cyclic AMP (cAMP) pathway

• Activated by Gs protein-coupled receptors, which stimulate adenylyl cyclase to convert ATP into cAMP
• cAMP activates protein kinase A (PKA), leading to the phosphorylation of downstream targets, such as ion channels, enzymes, and transcription factors
• Involved in the regulation of synaptic plasticity, gene expression, and cellular metabolism

Phospholipase C (PLC) pathway

• Activated by Gq protein-coupled receptors, which stimulate PLC to cleave phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)
• DAG activates protein kinase C (PKC), which phosphorylates various target proteins, while IP3 binds to receptors on the endoplasmic reticulum, causing the release of calcium from intracellular stores
• Involved in the regulation of synaptic plasticity, neurotransmitter release, and cell growth and differentiation

Mitogen-activated protein kinase (MAPK) pathway

• Activated by various receptors, including growth factor receptors (TrkB) and certain GPCRs
• Involves a series of phosphorylation events that lead to the activation of transcription factors (CREB, Elk-1) and changes in gene expression
• Plays a role in neuronal survival, differentiation, and synaptic plasticity

Rho GTPase pathway

• Activated by some GPCRs and regulates the actin cytoskeleton, cell adhesion, and cell migration
• Rho GTPases (RhoA, Rac1, Cdc42) act as molecular switches, cycling between active (GTP-bound) and inactive (GDP-bound) states
• Involved in the formation and maintenance of dendritic spines, axon guidance, and synaptic plasticity

Second messengers in signal amplification

Types and functions of second messengers

• Second messengers are small, diffusible molecules that relay and amplify signals from cell surface receptors to intracellular effector proteins
• Common second messengers include cyclic AMP (cAMP), cyclic GMP (cGMP), calcium ions (Ca2+), and lipid-derived molecules such as diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)
• Amplify signals by activating multiple effector proteins, such as protein kinases (PKA, PKC, CaMKII) and ion channels, leading to a cascade of biochemical reactions and a larger cellular response

Regulation of second messenger signaling

• The spatial and temporal regulation of second messenger production and degradation allows for the fine-tuning of cellular responses and the integration of multiple signaling inputs
• Second messengers can modulate the activity of signaling pathways by altering the sensitivity of receptors, the activity of effector proteins, or the expression of genes involved in the pathway
• The localization of second messenger-producing enzymes (adenylyl cyclase, phospholipase C) and degrading enzymes (phosphodiesterases) can create microdomains of signaling within the cell
• The duration and amplitude of second messenger signals can be controlled by the balance between production and degradation, as well as by the activity of downstream effector proteins