Endocrine II

Hormone Action Mechanisms

• Hormones act at a distance from the release site and need to travel in the blood, be soluble, survive long enough, and still be active at the target site.
• Hormones trigger specific actions in target cells through specific hormone-receptor recognition.
• The mode of action depends on the hormone's biochemical structure and its receptors.
• Receptors are essential for hormone action.
• Lipophilic hormones diffuse out of producing cells, circulate bound to carriers in the blood, then diffuse into target cells to interact with intracellular receptors.
• Water-soluble hormones are secreted by exocytosis, circulate free in the blood, and bind to surface receptors on target cells.

### Lipophilic Hormones (Steroids & Thyroid Hormones)

• Lipophilic hormones are insoluble in water and circulate bound to carrier proteins.
• Carrier proteins include specific globulins (CBG, DBG, SHBG, TBG) and non-specific proteins (albumin and prealbumin).
• Carrier proteins keep hormones in the bloodstream, prevent degradation, and serve as a hormone reservoir, buffer, and protection.
• A small portion of the hormone remains free and diffuses into tissues, representing the active form.
• Free hormones are susceptible to degradation and are involved in feedback loops.
• In general, carrier proteins help control the amount of free circulating hormones.

Action of Lipophilic Hormones

• Free hormones diffuse through the plasma membrane of target cells and bind to nuclear hormone receptors (NHRs), specific intracellular receptors.
• The hormone-receptor complex translocates to the nucleus and binds to DNA response elements to stimulate gene expression and de novo protein synthesis.
• NHRs act as transcription factors.
• Thyroid hormones, however, have NHRs already present in the nucleus.
• Lipophilic hormones are considered slow-acting because their action affects protein synthesis through gene regulation.

### Nuclear Hormone Receptors

• NHRs contain a ligand-binding domain, a DNA-binding domain, and an activation domain.
• Orphan receptors are cloned NHRs for which no ligand has yet been identified.

Water-Soluble Hormones (Proteins & Catecholamines)

• Water-soluble hormones cannot pass through the phospholipid membrane barrier.
• They are secreted in vesicles by exocytosis and circulate free in the blood.
• An exception is IGF-1, which circulates bound to a carrier protein.
• Water-soluble hormones bind to specific surface receptors on target cells, and do not enter the cell to act.
• They require second messengers to exert their effect.
• The receptor mediates interactions between the hormone and second messengers.

Cell Surface Receptor

• These receptors span the cell membrane, with a hydrophobic transmembrane domain and hydrophilic regions located outside (extracellular domain) and inside (intracellular domain) the cell.
• When a hormone binds to the receptor, it activates intracellular signaling pathways through second messengers.

Major Types of Cell Surface Receptors

• G-protein coupled receptors use adenylate cyclase and cAMP, phospholipase C and Ca2+, or other second messengers.
• Tyrosine kinase receptors trigger auto-phosphorylation.
• Interleukin/cytokine receptors rely on JAK-STAT signaling pathways.
• Serine kinase receptors (TGFβ family) utilize SMAD proteins.

G-Protein Coupled Receptors

• The hormone binds to a receptor coupled to G-proteins (αβγ subunits).
• The binding causes a conformational change in the receptor, leading to the exchange of GDP for GTP on the Gα subunit.
• The activated Gα subunit dissociates from the βγ subunits and activates a membrane protein.
• The activated membrane protein stimulates a cascade of second messengers.
• The second messengers elicit a biological response in the cell.

Adenylate Cyclase-cAMP-PKA Pathway

• Receptors linked to G-proteins αs or αi (e.g., β-adrenergic, LH) trigger this pathway.
• Adenylate cyclase (AC), a membrane-associated enzyme, is activated by αs and inhibited by αi.
• AC hydrolyzes ATP to produce cyclic AMP (cAMP).
• cAMP activates protein kinase A (PKA).
• Activated PKA phosphorylates intracellular proteins and stimulates gene transcription, resulting in a biological action.
• Phosphodiesterase degrades cAMP, and a phosphoprotein phosphatase deactivates PKA.

Phospholipase C Pathway (PLC)

• Receptors coupled to G-protein αq activate this pathway.
• PLC, a membrane-associated protein, is stimulated by αq.
• PLC hydrolyzes phosphoinositol diphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG).
• IP3 stimulates the release of Ca2+, while DAG activates protein kinase C (PKC).
• Ca2+/calmodulin and PKC initiate phosphorylation cascades, leading to a biological action.

Tyrosine Kinase Receptor

• Hormone binding activates the receptor, initiating auto-phosphorylation.
• The receptor acts as a kinase and phosphorylates tyrosines on target proteins.
• This pathway does not require second messengers like G-coupled proteins.
• The receptor consists of transmembrane, extracellular, and cytoplasmic domains.
• The cytoplasmic domain contains the auto-phosphorylation site, regulatory signals, and ATP binding sites.

Cytokine Receptors

• These receptors, which bind cytokines (e.g., GH, prolactin, erythropoietin, interferons, interleukins), lack intrinsic kinase activity.
• Hormone binding causes receptor dimerization and recruitment of JAK tyrosine kinase, which phosphorylates the receptor.
• Phosphotyrosines on the receptor act as docking sites for STATs (signal transducers and activators of transcription).
• STATs activate different genes.

Receptor Serine Kinase

• The TGFβ family (activin, inhibin, MIS) primarily controls cell proliferation and differentiation.
• Hormone binding leads to heterodimer formation between receptor I and receptor II.
• Receptor II, specific to the hormone, recruits receptor I.
• The same receptor I can be recruited by different receptor II complexes.
• The activated receptor phosphorylates SMAD proteins, which then dimerize, translocate to the nucleus, and modulate gene transcription.

Explore the intricate mechanisms by which hormones act on target cells. This quiz delves into the differences between lipophilic and water-soluble hormones, their modes of action, and the role of receptors in hormone activity. Test your understanding of how these biochemicals function in the body.