Fisiología Endocrina - INTRO (RECEPTORES HORMONALES - MECANISMO ACCIÓN) PARTE 3/3 (IG:@doctor.paiva)

Introduction to Endocrinology

Overview of Hormonal Action Mechanisms

• The class will cover generalities about hormone action mechanisms, focusing on G-protein coupled receptors, enzyme-linked receptors, and intracellular receptors.

• Hormones initiate their action by binding to specific receptors; cells lacking the appropriate receptor do not respond to the hormone.

• There are various types of hormone receptors located on cell membranes (e.g., insulin and catecholamine receptors), in the cytoplasm (e.g., cortisol), and in the nucleus (e.g., thyroid hormones).

Types of Receptors

• Receptors can be categorized into extracellular (membrane-bound) and intracellular (cytoplasmic or nuclear).

• Extracellular receptors include ion channel-linked, G-protein coupled, and enzyme-linked receptors. These typically bind non-lipid soluble hormones like protein-based hormones.

• Intracellular receptors are for lipid-soluble hormones that can cross cell membranes, such as steroid hormones and thyroid hormones.

Regulation of Receptor Sensitivity

• The number and sensitivity of hormonal receptors vary over time; they are not constant but fluctuate based on physiological needs.

• Receptors can be inactivated or destroyed while functioning or reactivated through new synthesis. This dynamic is crucial for maintaining hormonal balance.

Desensitization Mechanisms

• Desensitization refers to a decrease in receptor activity due to prolonged exposure to high hormone levels, leading to reduced receptor expression.

• Factors contributing to desensitization include internal signaling molecule inactivation, temporary sequestration of the receptor, or destruction after hormone binding.

Mechanism of Hormone Action

• The class will explore various mechanisms including ion channel-linked receptors which are less significant in endocrinology compared to neurology.

Understanding Hormonal Receptors and Their Mechanisms

Overview of Hormonal Receptors

• The discussion begins with the introduction of second messengers in hormonal signaling, specifically mentioning phospholipase C and calcium as key players.

• Receptors are categorized into two main types: ion channel-linked receptors (which can be chemically or voltage-dependent) and protein-coupled receptors.

Types of Protein-Coupled Receptors

• Protein-coupled receptors activate pathways such as adenylate cyclase, which increases cyclic AMP (cAMP), and phospholipase C, leading to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG).

• Hormonal receptors that are enzyme-linked include guanylate cyclase, receptor tyrosine kinases, and those associated with other catalytic enzymes.

Distinctions Among Enzyme-Linked Receptors

• There is a distinction between receptor tyrosine kinases that possess intrinsic kinase activity versus those that require an associated enzyme for their function.

• Tyrosine kinase receptors activate downstream signaling pathways like the Ras-MAPK pathway.

Intracellular Hormonal Receptors

• Intracellular hormone receptors include steroid hormones and thyroid hormones, which directly influence gene activation within cells.

• The classification includes extracellular receptors linked to ion channels, protein-coupled receptors, catalytic enzyme-linked receptors, and intracellular nuclear hormone receptors.

Mechanism of Ion Channel-Receptor Interaction

• Ion channel-linked receptors operate by allowing ions to flow through when a ligand binds; this process does not involve intermediaries like G-proteins.

• Non-lipid soluble hormones must bind to extracellular receptors since they cannot cross the cell membrane.

Voltage-Gated Ion Channels

• Voltage-gated ion channels open in response to changes in membrane potential; for example, sodium channels open during depolarization from -90mV to -65mV.

• Chemical-dependent ion channels respond directly to specific ligands without intermediary proteins.

Mechanisms of Acetylcholine and G-Protein Coupled Receptors

Acetylcholine and Sodium Channels

• Acetylcholine binds to nicotinic receptors at the neuromuscular junction, leading to sodium channel opening.

• Nicotinic receptors facilitate rapid responses by allowing sodium influx upon acetylcholine binding, while muscarinic receptors operate through different mechanisms.

G-Protein Coupled Receptors (GPCRs)

• GPCRs consist of three subunits: alpha, beta, and gamma. The inactive state is characterized by the alpha subunit being bound to GDP.

• Activation occurs when a ligand binds to the receptor, causing GDP to be replaced with GTP on the alpha subunit, which then dissociates from beta and gamma.

Signal Transduction Mechanism

• The activated alpha subunit migrates within the cell, triggering various intracellular pathways.

• This migration allows for activation of enzymes such as adenylate cyclase or phospholipase C, which play crucial roles in cellular signaling.

Enzyme Activation and Effects

• Adenylate cyclase converts ATP into cyclic AMP (cAMP), a secondary messenger that activates protein kinases.

• Phospholipase C generates inositol trisphosphate (IP3) and diacylglycerol (DAG), leading to calcium release from stores and further signaling cascades.

Types of G Proteins

• Different types of G proteins (Gs, Gi, Gq) have distinct effects; for example:

• Gs stimulates adenylate cyclase increasing cAMP levels.

• Gi inhibits adenylate cyclase decreasing cAMP levels.

• Gq activates phospholipase C leading to IP3 production.

Potassium Channels and Action Potential

• Activation of potassium channels can lead to hyperpolarization of the cell membrane during action potentials due to potassium efflux.

• Understanding these dynamics is essential for grasping how neurotransmitters influence neuronal excitability.

Role of Protein Kinases

• Protein kinases activated by cAMP phosphorylate target proteins affecting various cellular functions including gene transcription.

Mechanisms of cAMP and Protein Kinase Regulation

Role of Phosphodiesterase in cAMP Regulation

• Phosphodiesterase is crucial for controlling cyclic AMP (cAMP) levels in the cytoplasm, preventing its persistence.

• Inhibition of phosphodiesterase by drugs like caffeine and theophylline leads to increased cAMP levels, affecting cellular responses.

• Sildenafil also inhibits phosphodiesterase, highlighting its role in regulating cGMP alongside cAMP.

Functionality of Protein Kinases

• Protein kinases consist of regulatory and catalytic subunits; binding with cAMP activates the catalytic subunits.

• The dissociation of regulatory units allows protein kinases to phosphorylate target proteins, influencing various cellular functions.

• Protein phosphatase 1 regulates dephosphorylation, maintaining a balance between phosphorylation and dephosphorylation processes.

Hormonal Influence on Cellular Mechanisms

• Hormones such as TSH, ACTH, and ADH utilize G-protein coupled receptors to modulate intracellular signaling pathways.

• Increased cAMP from TSH stimulates thyroid hormone production; ACTH promotes steroid hormone secretion from adrenal glands.

• ADH enhances water permeability in kidney tubules through similar mechanisms involving receptor activation.

Diverse Effects Mediated by cAMP

• Different hormones can activate distinct receptors leading to varied effects despite all utilizing cAMP as a second messenger.

• For instance, adrenaline and glucagon trigger different physiological responses via their respective pathways linked to cAMP.

G-protein Activation and Its Consequences

• G-proteins inhibit adenylate cyclase when activated by hormone-receptor binding, reducing cAMP synthesis.

• Activation of potassium channels through G-proteins results in hyperpolarization effects on cardiac cells mediated by muscarinic receptors.

Pathways Activated by Phospholipase C

• Gq proteins activate phospholipase C instead of adenylate cyclase, leading to different signaling cascades within cells.

• Phospholipase C cleaves membrane lipids producing diacylglycerol (DAG), which activates protein kinase C (PKC).

Calcium Mobilization Through IP3

• Inositol trisphosphate (IP3), generated during phospholipase C activity, opens calcium channels in the endoplasmic reticulum and mitochondria.

Calcium Signaling and Muscle Contraction

Calcium Channels and Second Messengers

• Calcium is released from the membrane, activating inositol triphosphate (IP3) which opens calcium channels in the endoplasmic reticulum and mitochondria. This intracellular calcium acts as a second messenger, potentially activating protein kinases for various physiological actions.

• The interaction of calcium with calmodulin is crucial; unlike skeletal muscle that relies on troponin, smooth muscle contraction depends on calcium-calmodulin complexes.

Receptor Activation Mechanisms

• Inactive G-protein coupled receptors can be activated by adrenaline and noradrenaline binding to adrenergic receptors (alpha 1, alpha 2, beta 1, beta 2). Each receptor type utilizes different G-proteins affecting cyclic AMP levels.

• Understanding these receptor mechanisms is essential as they dictate physiological responses based on cyclic AMP modulation. For instance, alpha 1 receptors activate phospholipase C while beta receptors increase cyclic AMP levels.

Hormonal Influence on Signal Transduction

• Hormones like calcitonin utilize adenylate cyclase pathways through G-protein coupled receptors to influence cellular functions. Phosphodiesterase inhibitors such as caffeine enhance cyclic AMP persistence.

• The role of calcium in metabolic actions is emphasized through its interactions with second messengers like IP3 and diacylglycerol (DAG), highlighting the complexity of signaling pathways involving multiple hormones.

Types of Receptors and Their Functions

• Different types of hormone receptors include those coupled to enzymes or catalytic activities such as guanylate cyclase and tyrosine kinase. These play distinct roles in signal transduction processes.

• Guanylate cyclase responds to hormones like atrial natriuretic peptide (ANP), converting GTP into cyclic GMP (cGMP), which mediates various physiological effects including vasodilation.

Specific Actions of cGMP

• cGMP serves as a second messenger for hormones acting via guanylate cyclase, influencing processes such as smooth muscle relaxation and diuresis through ANP action.

Mechanisms of Hormonal Action and Receptor Function

Transformation of GTP to Cyclic GMP

• Ciclasa transforms GTP into cyclic GMP (cGMP), which induces relaxation in smooth muscle due to the action of nitric oxide, a known vasodilator.

Tyrosine Kinase Receptors

• Tyrosine kinase receptors possess enzymatic activity with two extracellular alpha subunits linked by covalent bonds to beta subunits. Upon hormone binding, these receptors undergo dimerization and activation.

• The activated receptor auto-phosphorylates on tyrosine residues, facilitating energy transfer through phosphate groups to enzymes and proteins that perform specific functions based on the type of hormone involved.

Signaling Pathways Activated by Receptors

• These receptors can activate ion channels or phospholipases, leading to gene expression changes within the nucleus. They primarily operate via the Ras-MAPK signaling pathway.

• Other receptors lack intrinsic tyrosine kinase activity but are coupled with kinases like JAK, which also leads to auto-phosphorylation and subsequent genetic regulation.

Hormones Utilizing Specific Pathways

• Growth hormones differ from growth factors; for instance, growth hormone, prolactin, and leptin utilize pathways involving JAK kinases for their physiological effects.

• The JAK pathway is crucial for gene regulation and protein synthesis following hormonal stimulation.

Types of Hormonal Receptors

• There are various types of catalytic receptors including guanylate cyclase and serine/threonine kinases. Insulin utilizes these pathways alongside leptin and growth hormones.

Lipophilic Hormones Mechanism

• Lipophilic hormones pass through cell membranes due to their solubility. Steroid hormones bind cytoplasmic receptors before entering the nucleus directly or as a complex.

• Once inside the nucleus, they bind specific DNA elements activating transcription processes that lead to mRNA formation.

Transcription and Translation Process

• The hormone-receptor complex binds DNA at promoter regions causing transcription activation. This results in mRNA exiting the nucleus for translation at ribosomes in rough endoplasmic reticulum.

Hormonal Mechanisms and Receptor Types

Overview of Hormone Action

• Hormones such as retinoids, thyroid hormones (T3 and T4), and vitamin D act through nuclear receptors, which are crucial for their function.

• Lipophilic hormones can bind to cytoplasmic proteins, forming a complex that translocates to the nucleus to initiate transcription and translation via messenger RNA.

Mechanism of Lipophilic Hormones

• Lipophilic hormones diffuse into cells, binding to specific nuclear receptors or cytoplasmic proteins. For example, aldosterone binds to mineralocorticoid receptors before entering the nucleus to exert its effects.

Types of Hormone Receptors

• Various hormone types utilize different receptor mechanisms:

• Catalytic Receptors: Include natriuretic peptide, nitric oxide, insulin, and growth factors using the Ras-MAPK pathway.

• Tyrosine Kinase Receptors: Involve growth hormone, prolactin, and leptin signaling pathways.

Intracellular vs. Membrane-bound Receptors

• Steroid hormones (e.g., glucocorticoids), thyroid hormones (T3/T4), and retinoids use intracellular receptors. Understanding these distinctions is vital for comprehending hormonal actions.

Upcoming Topics in Endocrinology

• Future discussions will focus on specific hormones like aldosterone's action mechanism and detailed exploration of hypothalamic-pituitary axes along with various endocrine glands including thyroid and adrenal glands.

References for Further Reading

• Suggested readings include "Gayton's Physiology" and "Biological Chemistry" by Antonio Blanco for comprehensive understanding of hormonal physiology.

Closing Remarks