messenger receptors
Chronic Exercise and Hormonal Release
Chronic exercise stimulates the release of cortisol, a steroid hormone, from the adrenal cortex. Concurrently, the exercise of jogging increases the secretion of epinephrine and norepinephrine from the adrenal medulla. Each hormone is released in response to specific signals and elicits characteristic responses in target tissues, which enable physical activity. Each hormone binds to different types of receptors and operates via distinct mechanisms.
General Features of Chemical Messengers
Chemical messenger systems have specific universal characteristics, detailed in Figure 11.1:
Secretion of Messenger: The chemical messenger is secreted from specific cells in response to a stimulus.
Transport to Target Cells: The messenger diffuses or is transported through the blood or other extracellular fluid to the target cell.
Binding to Receptors: A molecule in the target cell, termed a receptor (which can be a plasma membrane receptor or an intracellular receptor), specifically binds the messenger.
Elicitation of Response: The binding of the messenger to the receptor triggers a cellular response.
Termination of Signal: The signal eventually ceases and is terminated.
Chemical messengers elicit their responses in target cells without being metabolized by those cells. The specificity of the response is determined by the type of receptor and its location. Generally, each receptor is designed to bind only one specific chemical messenger and initiates a designated signal transduction pathway that activates or inhibits various processes within the cell. Only specific target cells possess the receptors needed to respond to the messenger.
Glucagon as a Chemical Messenger
For instance, during fasting, high levels of glucagon are present. This endocrine hormone is secreted in response to low blood glucose levels. It enters the blood and acts on the liver, stimulating several pathways, including the release of glucose from glycogen stores (glycogenolysis). The specificity of glucagon's action is determined by where its receptors are located. Liver parenchymal cells contain glucagon receptors, while skeletal muscle and many other tissues do not, meaning glucagon cannot stimulate glycogenolysis in those tissues.
Importance of Signal Termination
Signal termination is crucial in cell signaling. Failure to terminate signals appropriately can contribute to diseases, including cancer.
Example: Nicotinic Acetylcholine Receptor
Overview of Acetylcholine Signaling
The steps involved in chemical messenger signaling are illustrated using acetylcholine (ACh), a neurotransmitter acting on nicotinic acetylcholine receptors on the plasma membrane of certain muscle cells. This system demonstrates classic features of chemical messenger release and specificity of response.
Neurotransmitter Release: Neurotransmitters are secreted from neurons when an electrical stimulus, known as the action potential, occurs (resulting from voltage changes across the plasma membrane driven by Na+ and K+ gradients).
Diffusion Across Synapse: The neurotransmitter diffuses across a synapse to elicit a response in another excitable cell. ACh is the neurotransmitter at neuromuscular junctions, facilitating the signaling from a motor nerve to a muscle fiber, prompting the muscle contraction.
Vesicle Release Mechanism: Prior to release, ACh is stored in vesicles aggregated near the presynaptic membrane, which has voltage-gated Ca²+ channels. When the action potential arrives, the channels open, allowing Ca²+ influx. The increase in Ca²+ concentration induces vesicle fusion with the plasma membrane, resulting in ACh release into the synaptic cleft.
Synaptic Components
Synaptic Vesicles: Contain ACh.
Presynaptic Membrane: Site of vesicle release.
Postsynaptic Membrane: Contains nicotinic ACh receptors.
Junctional Folds: Increased receptor concentration.
Mechanism of Action
ACh diffuses across the synaptic cleft and binds to nicotinic ACh receptors on muscle cells. Each receptor consists of five subunits, assembled around a channel with a funnel-like opening. When ACh binds, conformational changes occur, opening the channel to allow Na+ to enter and K+ to exit. This change in ion concentration triggers further cellular responses, culminating in muscle fiber contraction.
Disease Example: Myasthenia Gravis
Myasthenia gravis is an autoimmune disease characterized by the production of antibodies against nicotinic ACh receptors in skeletal muscle. This results in fewer functional ACh receptors, leading to muscle weakness.
Termination of ACh: Once ACh secretion stops, acetylcholinesterase on the postsynaptic membrane rapidly cleaves ACh, thereby terminating the signal. ACh can also diffuse away from the synapse, contributing to rapid message termination, crucial for systems requiring quick responses.
Classification of ACh Receptors
ACh acts on two receptor types:
Nicotinic Receptors: Found at neuromuscular junctions in skeletal muscle and in the parasympathetic nervous system, activated by nicotine.
Muscarinic Receptors: Found at cardiac and smooth muscle junctions, activated by muscarine (a toxin).
Antagonists: Curare is a block for nicotinic receptors, while atropine inhibits muscarinic receptors. Atropine can block effects of excess ACh during conditions of acetylcholinesterase inactivation.
Actions of Chemical Messengers
Chemical messenger actions can be classified as endocrine, paracrine, or autocrine:
Endocrine: Hormones like insulin secreted from endocrine glands into the bloodstream affecting distant target cells.
Paracrine: Actions affecting nearby cells, such as synaptic transmission by neurotransmitters like ACh.
Autocrine: Messengers acting on, or near, the cell that secretes them, especially when they are of the same type.
Example: Edrophonium Chloride in Myasthenia Gravis
Mia S. could be treated with edrophonium chloride, an acetylcholinesterase inhibitor. This drug increases local ACh concentration, briefly improving muscular weakness despite fewer functional receptors.
Types of Chemical Messengers
Chemical messengers have major categorizations based on the systems that employ them:
Nervous System: Secretes small-molecule neurotransmitters (biogenic amines) and neuropeptides. Examples include:
Acetylcholine
Epinephrine
Gamma-aminobutyric acid (GABA)
Neuropeptides are small peptides (4-35 amino acids) acting as neurotransmitters or neurohormones.
Endocrine System: This includes hormones secreted from specific cells in endocrine organs. Hormones like insulin (secreted from B-cells in the pancreas) are common, classified into groups such as polypeptides, catecholamines (e.g., epinephrine), steroid hormones, and thyroid hormones. Many hormones also exhibit paracrine or autocrine properties.
Example of Complex Categorization: Retinoids (vitamin A derivatives) and vitamin D can be classified as hormones, despite not being synthesized in endocrine cells.
Immune System: Messengers known as cytokines are proteins with a molecular weight around 20,000 Da that regulate immune responses against microorganisms. They include interleukins, tumor necrosis factors, and chemokines, which induce targeted cell movement.
Catecholamines: Epinephrine and Norepinephrine
Epinephrine, also called adrenaline, acts as the "fight or flight" hormone released during stress responses, with norepinephrine acting similarly. Their release from the adrenal medulla responds to stressors like exercise and pain.
Eicosanoids
Eicosanoids, derived from arachidonic acid (a 20-carbon polyunsaturated fatty acid), control cellular responses to injury. This group includes prostaglandins (PG), thromboxanes, and leukotrienes, primarily function through paracrine and autocrine signaling, affecting nearby or producing cells.
Example of Eicosanoid Function
Vascular endothelial cells produce prostaglandin PGI2, which induces vasodilation in smooth muscle cells.
Growth Factors
Growth factors are polypeptides stimulating cellular proliferation or size. An example is platelet-derived growth factor (PDGF) secreted by platelets at injury sites, stimulating the proliferation of smooth muscle cells and forming plaques over injuries. Some growth factors are classified as hormones, while others are termed cytokines.
Intracellular Receptors and Signal Transduction
Intracellular versus Plasma Membrane Receptors
Receptors can be categorized into intracellular receptors or plasma membrane receptors based on their structural properties and the nature of their bound messengers. Intracellular receptors typically bind hydrophobic molecules that diffuse through membranes, while plasma membrane receptors bind polar molecules unable to cross membranes directly.
Overview of Lipophilic Hormones
The primary lipophilic hormones (including steroid and thyroid hormones) bind to intracellular gene-specific transcription factors, which regulate gene expression. These receptors, part of a superfamily, can exist in cytoplasm or nucleus.
Example of Cortisol Action
Cortisol, released from the adrenal cortex, affects tissues by modifying enzyme levels and redistributing nutrients during stress. It increases transcription of gluconeogenic enzyme genes, enhancing liver gluconeogenesis.
Plasma Membrane Receptors and Their Signal Transduction Mechanisms
Plasma membrane receptors are proteins with distinct features leading to signal transduction pathways:
Structure: Main features include extracellular domains for ligand binding, transmembrane domains, and intracellular domains for initiating signal transduction.
Types:
Ion-Channel Receptors: Allow Ions to traverse membranes upon ligand binding, resembling nicotinic ACh receptors.
Kinase Receptors: These receptors, such as tyrosine kinases, transfer phosphate groups from ATP to target proteins, signaling downstream changes.
Heptahelical Receptors: G-protein coupled receptors (GPCRs) decipher messages via second messengers like cAMP, relaying signals within cells.
Eicosanoids Derived from Arachidonic Acid
Eicosanoids play a key role in signaling, acting through paracrine and autocrine systems, ultimately facilitating cellular functions related to injury responses.
Summary of Signal Transduction via Plasma Membrane Receptors
Signal transduction pathways elicit rapid effects on cellular functions or slow changes in gene expression, often producing both due to cascading events.
Example of Insulin Receptor Signaling
The insulin receptor exemplifies the complexity of tyrosine kinase signaling. The binding of insulin activates autophosphorylation, allowing recruitment of insulin receptor substrates (IRS), leading to diverse signalling pathways affecting glucose metabolism and cell survival.
Conclusion
Understanding chemical messengers and their signaling pathways is essential in comprehending various physiological processes, including metabolism, immune responses, and cellular communication. Each signaling mechanism has distinct features that enable precise regulation and response to environmental changes.