Intracellular Receptors and Signal Transduction

Intracellular Receptors

• Hydrophobic and lipophilic steroid and thyroid hormones pass through the cell membrane by passive diffusion
• Some bind to receptors in the cytoplasm, while others cross the nuclear membrane and bind to receptors in the nucleus
• Androgen, glucocorticoid, and mineralocorticoid receptors are located in the cytoplasm
• Estrogen, progesterone, thyroid hormone, and vitamin receptors are located in the nucleus

Signal Transduction

• Activated hormone-receptor complex can act as a transcription factor by binding to special DNA sequences (hormone response element, HRE) in the nucleus
• Unlike cell surface receptors, intracellular receptors generally exert their effects directly without using a secondary messenger

Steroid Hormones

• Steroid hormones, such as corticosteroids, are produced in the adrenal gland and influence the metabolism of many types of cells
• Steroid sex hormones, such as testosterone, estrogen, and progesterone, are made in the testes and ovaries
• Vitamin D3 is synthesized in the skin in response to sunlight and regulates Ca2+ metabolism

cAMP Signaling

• The ligand interacts with the G-protein-coupled receptor (GPCR) and activates the enzyme Adenylate cyclase (effector protein) in the membrane
• Adenylate cyclase converts ATP to cAMP to activate protein kinase A (target)
• Protein kinase A performs phosphorylation of other molecules inside the cell
• cAMP levels in the cell are reduced by the conversion of cAMP+H2O to AMP with the phosphodiesterase enzyme

cAMP Signaling in Muscle Cells

• Adrenaline in muscle cells binds to β adrenergic receptors, increasing cAMP and activating protein kinase A
• Protein kinase A phosphorylates and activates phosphorylase kinase, which breaks down glycogen to glucose
• Glycogen synthesis stops, and glucose levels in the blood increase

cAMP Signaling in Gene Transcription

• The transcription factor CREB (CRE binding protein) initiates the transcription of specific genes
• The catalytic subunit of cAMP-activated Protein Kinase A detaches and passes into the nucleus and activates the CREB protein by phosphorylating
• CREB transcription factor leads to transcription of various genes (DNA → mRNA)

cGMP Signaling

• cGMP is formed by guanylate cyclase and degraded by cGMP phosphodiesterase
• cGMP is involved in visual signal transmission in vertebrates
• Nitric oxide (NO) and ANP (atrial natriuretic peptide) increase intracellular cGMP levels by activating guanylate cyclase

Nitric Oxide Signaling

• Nitric oxide is produced from arginine amino acid by nitric oxide synthetase (NOS) enzyme
• NO can easily enter the cell by diffusion through the cell membrane
• NO causes relaxation in the smooth muscle and endothelial cells of the coronary vessels, allowing a greater amount of blood to flow to the heart muscle
• NO stimulates the aggregation of platelets, playing a role in coagulation

Calcium Signaling

• One of the Ca/Calmodulin-dependent protein kinases stimulates muscle contraction by phosphorylating the myosin protein and stimulating the interaction between actin–myosin for muscle contraction
• Other Ca/Calmodulin-dependent protein kinases (CaM kinases) phosphorylate various metabolic enzymes, ion channels, and transcription factors (CREB)
• They stimulate the release of neurotransmitters in the central nervous system