Pathways

Nitric oxide pathway, step 1 of 8. Context: acetylcholine (ACh) is released near a blood vessel. What is the first step? ACh binds muscarinic ACh receptors (G protein-coupled receptors) on the endothelial cells lining the vessel.

Nitric oxide pathway, step 2 of 8. Step 1: ACh binds muscarinic receptors on endothelial cells. What happens next? Receptor activation causes production of IP3.

Nitric oxide pathway, step 3 of 8. Step 2: IP3 is produced in the endothelial cell. What happens next? IP3 opens Ca2+ channels on the ER membrane, releasing Ca2+ into the cytoplasm.

Nitric oxide pathway, step 4 of 8. Step 3: Ca2+ is released into the endothelial cell's cytoplasm. What happens next? Ca2+ stimulates the enzyme NO synthase.

Nitric oxide pathway, step 5 of 8. Step 4: Ca2+ activates NO synthase. What happens next? NO synthase makes nitric oxide gas (NO) from the amino acid arginine.

Nitric oxide pathway, step 6 of 8. Step 5: NO synthase makes NO from arginine. What happens next? NO diffuses out of the endothelial cell into the neighboring smooth muscle cells, where it activates guanylyl cyclase. NO only reaches neighbors (paracrine) because it's quickly converted to nitrates and nitrites.

Nitric oxide pathway, step 7 of 8. Step 6: NO activates guanylyl cyclase in the smooth muscle cell. What happens next? Guanylyl cyclase converts GTP into cGMP + PPi.

Nitric oxide pathway, step 8 of 8. Step 7: Guanylyl cyclase makes cGMP. What happens next? cGMP promotes smooth muscle relaxation, so the blood vessel relaxes (dilates).

Insulin pathway, step 1 of 9. Context: blood glucose is high, and insulin is released. What is the first step? Insulin binds the insulin receptor on the outside of the cell.

Insulin pathway, step 2 of 9. Step 1: Insulin binds its receptor. What happens next? The receptor's intracellular kinase domains phosphorylate the receptor itself (autophosphorylation).

Insulin pathway, step 3 of 9. Step 2: The receptor phosphorylates itself. What happens next? The phosphorylated receptor binds and phosphorylates signaling (docking) proteins and transcription factors, passing the signal into the cell.

Insulin pathway, step 4 of 9. Step 3: The receptor phosphorylates signaling proteins. What happens next in the glucose-uptake branch? Vesicles carrying GLUT4 transporters move to the plasma membrane and fuse with it, inserting GLUT4.

Insulin pathway, step 5 of 9. Step 4: GLUT4 is inserted into the plasma membrane. What happens next? Glucose enters the cell through GLUT4 by facilitated diffusion (no ATP). This is the short-term effect.

Insulin pathway, step 6 of 9. Step 3: The receptor phosphorylates a transcription factor. What does that transcription factor do next? It moves into the nucleus to change gene expression.

Insulin pathway, step 7 of 9 (second messenger branch). Step 3: The receptor activates signaling proteins. What second messengers are made, and what do they do? PIP2 is converted to IP3 and DAG, which activate a transcription factor that goes to the nucleus.

Insulin pathway, step 8 of 9 (kinase cascade branch). Step 3: The receptor activates signaling proteins. What kinase cascade follows? MEK → MAPK → Erk → the transcription factor Elk, which goes to the nucleus.

Insulin pathway, step 9 of 9. Steps 6–8: Transcription factors reach the nucleus. What happens next? They turn on transcription of DNA into mRNA, changing gene expression. This is the long-term effect.

Insulin kinase cascade: what comes right after MEK? MAPK.

Insulin kinase cascade: what comes right after MAPK? Erk.

Insulin kinase cascade: what comes right after Erk? The transcription factor Elk, which changes gene expression in the nucleus.

Phosphoinositide (angiotensin II) pathway, step 1 of 7. Context: the hormone angiotensin II reaches vascular smooth muscle to raise blood pressure. What is the first step? Angiotensin II binds its receptor (a G protein-coupled receptor) on the vascular smooth muscle cell.

Phosphoinositide pathway, step 2 of 7. Step 1: Angiotensin II binds its receptor. What happens next? The receptor activates a G protein (GDP swapped for GTP), and the G protein activates phospholipase C (PLC).

Phosphoinositide pathway, step 3 of 7. Step 2: The G protein activates phospholipase C. What happens next? Phospholipase C cuts PIP2 (a membrane lipid) into IP3 and DAG. IP3 is released into the cytoplasm, and DAG stays in the membrane.

Phosphoinositide pathway, step 4 of 7. Step 3: PLC cuts PIP2 into IP3 and DAG. What does IP3 do next? IP3 diffuses to the smooth ER and binds and opens Ca2+ channels in the ER membrane.

Phosphoinositide pathway, step 5 of 7. Step 4: IP3 opens Ca2+ channels on the smooth ER. What happens next? Ca2+ flows out of the ER lumen (high Ca2+) into the cytoplasm, down its gradient.

Phosphoinositide pathway, step 6 of 7. Step 5: Ca2+ floods into the cytoplasm. What happens next? Ca2+ and DAG (in the membrane) together activate protein kinase C (PKC).

Phosphoinositide pathway, step 7 of 7. Step 6: Ca2+ and DAG activate protein kinase C. What happens next? PKC causes vasoconstriction (the smooth muscle contracts), which raises blood pressure.