Action Mechanism

Understanding how hormones work at the cellular level is key to understanding endocrinology. Hormones initiate their effects by binding to receptors, triggering a cascade of intracellular events

Hormone Receptors

Definition: Proteins located either on the cell surface or within the cell that bind to specific hormones, initiating a cellular response
Types of Receptors
- Cell Surface Receptors: Typically bind to peptide hormones and catecholamines
  - G Protein-Coupled Receptors (GPCRs): Activate intracellular signaling pathways through G proteins
  - Receptor Tyrosine Kinases (RTKs): Initiate phosphorylation cascades, leading to altered gene expression and cellular function
  - Cytokine Receptors: Activate intracellular signaling pathways through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs)
- Intracellular Receptors: Located in the cytoplasm or nucleus, typically bind to steroid hormones and thyroid hormones
  - Nuclear Receptors: Regulate gene transcription by binding to DNA response elements

Mechanisms of Hormone Action

Peptide Hormones and Catecholamines
- Binding to Cell Surface Receptors:
  - Hormone binds to a specific receptor on the cell membrane
  - Receptor undergoes a conformational change, activating intracellular signaling pathways
- Activation of G Proteins:
  - GPCRs activate G proteins (Gs, Gi, Gq)
  - Gs stimulates adenylyl cyclase, increasing cAMP levels
  - Gi inhibits adenylyl cyclase, decreasing cAMP levels
  - Gq activates phospholipase C, increasing IP3 and DAG levels
- Activation of Second Messengers:
  - cAMP activates protein kinase A (PKA), which phosphorylates target proteins, altering their activity
  - IP3 releases calcium from the endoplasmic reticulum, activating protein kinase C (PKC) and other calcium-dependent signaling pathways
  - DAG activates PKC, which phosphorylates target proteins
- Activation of Receptor Tyrosine Kinases (RTKs):
  - Hormone binding causes receptor dimerization and autophosphorylation
  - Phosphorylated tyrosine residues recruit intracellular signaling proteins, such as SH2 domain-containing proteins
  - Activation of downstream signaling pathways, including the MAPK/ERK pathway and the PI3K/Akt pathway
- Signal Amplification:
  - The initial hormone-receptor interaction is amplified through signaling cascades, leading to a large cellular response
- Cellular Response:
  - Changes in enzyme activity, gene expression, and cellular function
Steroid Hormones and Thyroid Hormones
- Entry into the Cell:
  - Hormone diffuses across the cell membrane and enters the cytoplasm
- Binding to Intracellular Receptors:
  - Hormone binds to a specific receptor in the cytoplasm or nucleus
  - Receptor undergoes a conformational change, forming a hormone-receptor complex
- Translocation to the Nucleus (if receptor is cytoplasmic):
  - Hormone-receptor complex translocates to the nucleus
- Binding to DNA:
  - Hormone-receptor complex binds to specific DNA response elements (HREs) in the promoter region of target genes
- Regulation of Gene Transcription:
  - The hormone-receptor complex recruits coactivator or corepressor proteins, altering gene transcription
  - Increased transcription leads to increased mRNA synthesis and protein production
  - Decreased transcription leads to decreased mRNA synthesis and protein production
- Cellular Response:
  - Changes in protein synthesis and cellular function

Detailed Mechanisms

G Protein-Coupled Receptors (GPCRs)
- Structure:
  - GPCRs are transmembrane proteins with seven transmembrane domains
  - The extracellular domain binds to the hormone, while the intracellular domain interacts with G proteins
- Activation:
  - Hormone binding causes a conformational change in the receptor, activating the associated G protein
  - G proteins consist of three subunits: alpha, beta, and gamma
  - The alpha subunit binds to GTP and has intrinsic GTPase activity
  - Activation of the G protein causes the alpha subunit to dissociate and activate or inhibit downstream effectors
- Downstream Effectors:
  - Adenylyl cyclase: Stimulated by Gs, inhibited by Gi
    - Adenylyl cyclase catalyzes the conversion of ATP to cAMP
    - cAMP activates protein kinase A (PKA)
  - Phospholipase C: Activated by Gq
    - Phospholipase C catalyzes the hydrolysis of PIP2 to IP3 and DAG
    - IP3 releases calcium from the endoplasmic reticulum
    - DAG activates protein kinase C (PKC)
- Termination of Signal:
  - The intrinsic GTPase activity of the G protein alpha subunit hydrolyzes GTP to GDP, inactivating the G protein
  - Phosphodiesterases degrade cAMP, reducing PKA activity
  - Calcium pumps remove calcium from the cytoplasm, reducing PKC activity
Receptor Tyrosine Kinases (RTKs)
- Structure:
  - RTKs are transmembrane proteins with an extracellular domain that binds to the hormone and an intracellular domain with tyrosine kinase activity
- Activation:
  - Hormone binding causes receptor dimerization and autophosphorylation of tyrosine residues in the intracellular domain
  - Phosphorylated tyrosine residues serve as docking sites for intracellular signaling proteins with SH2 domains
- Downstream Signaling Pathways:
  - MAPK/ERK Pathway:
    - Activated by growth factors, such as epidermal growth factor (EGF)
    - Involves a cascade of protein kinases: Ras -> Raf -> MEK -> ERK
    - ERK phosphorylates transcription factors, altering gene expression
  - PI3K/Akt Pathway:
    - Activated by insulin and growth factors
    - Involves phosphatidylinositol 3-kinase (PI3K) and Akt
    - Akt promotes cell survival, growth, and metabolism
- Termination of Signal:
  - Protein phosphatases remove phosphate groups from tyrosine residues, inactivating the receptor
  - GTPase-activating proteins (GAPs) inactivate Ras by promoting GTP hydrolysis
Nuclear Receptors
- Structure:
  - Nuclear receptors are intracellular proteins with a DNA-binding domain and a ligand-binding domain
  - The DNA-binding domain contains zinc finger motifs that recognize specific DNA sequences (response elements)
- Activation:
  - Hormone enters the cell and binds to the receptor, causing a conformational change
  - The hormone-receptor complex translocates to the nucleus (if the receptor is cytoplasmic)
- Regulation of Gene Transcription:
  - The hormone-receptor complex binds to specific DNA response elements (HREs) in the promoter region of target genes
  - Recruitment of Coactivators:
    - Coactivators are proteins that enhance gene transcription
    - They include histone acetyltransferases (HATs), which modify chromatin structure to make DNA more accessible
  - Recruitment of Corepressors:
    - Corepressors are proteins that inhibit gene transcription
    - They include histone deacetylases (HDACs), which modify chromatin structure to make DNA less accessible
- Termination of Signal:
  - Hormone dissociates from the receptor, inactivating the complex
  - Protein phosphatases remove phosphate groups from transcription factors

Examples of Hormones and Their Mechanisms of Action

Insulin: Binds to receptor tyrosine kinase, activating the PI3K/Akt pathway and promoting glucose uptake
Glucagon: Binds to G protein-coupled receptor, activating adenylyl cyclase and increasing cAMP levels
Epinephrine: Binds to adrenergic receptors (GPCRs), activating adenylyl cyclase or phospholipase C
Cortisol: Binds to intracellular glucocorticoid receptor, regulating gene transcription
Thyroid Hormone: Binds to intracellular thyroid hormone receptor, regulating gene transcription

Clinical Significance

Drug Development: Understanding hormone receptor signaling pathways is crucial for developing drugs that target specific hormone-related disorders
- Agonists: Drugs that activate hormone receptors
- Antagonists: Drugs that block hormone receptors
Hormone Resistance: Mutations in hormone receptors can lead to hormone resistance, where target tissues fail to respond normally to hormones
Cancer: Aberrant hormone signaling can contribute to cancer development and progression
Autoimmune Disorders: In some autoimmune disorders, antibodies target hormone receptors, leading to either overstimulation or blockade of hormone signaling

Key Terms

Hormone Receptor: A protein that binds to a specific hormone
Cell Surface Receptor: A receptor located on the cell membrane
Intracellular Receptor: A receptor located within the cell
G Protein-Coupled Receptor (GPCR): A receptor that activates intracellular signaling pathways through G proteins
Receptor Tyrosine Kinase (RTK): A receptor that initiates phosphorylation cascades
Second Messenger: An intracellular signaling molecule, such as cAMP, IP3, or DAG
Protein Kinase: An enzyme that phosphorylates proteins
Transcription Factor: A protein that regulates gene transcription
DNA Response Element (HRE): A specific DNA sequence that binds to hormone-receptor complexes
Agonist: A drug that activates a hormone receptor
Antagonist: A drug that blocks a hormone receptor
Hormone Resistance: A condition where target tissues fail to respond normally to a hormone due to receptor defects or post-receptor signaling abnormalities
Autophosphorylation: The phosphorylation of a protein by itself
Dimerization: The formation of a complex between two identical proteins

Physiology

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