Lecture 15: Receptors and Cell Signaling

Question 1

Endocrine signaling

Answer 1

• hormone transported via blood
  ex: epinephrine
• long-distance, long lasting, freely diffusing signal

Question 2

Paracrine signaling

Answer 2

• diffuses to neighboring target cell of different type
  ex: testosterone (leydig cells –> sertoli cells/germ cells)
• local signaling, short-lived signals

Question 3

Autocrine signaling

Answer 3

• secreting cells express surface receptors for signal
  ex: IL-1 (T-lymphocyte produced; stim T cell replication)
• CANCER CELLS

Question 4

Direct (juxtacrine) signaling

Answer 4

• signal binds to signaling cell which binds to receptor on target cell
  ex: heparin-binding epidermal growth factor (HB-EFG)
• in immune cells

Question 5

Hydrophilic Signaling

Answer 5

• cannot penetrate plasma membrane, creates second messenger molecule (downstream cellular response)
  ex: epinephine, glucagon, insulin

Receptors: G-coupled proteins, receptor tyrosine kinase

Question 6

Lipophilic Signaling

Answer 6

• pass through plasma membrane of target cell
  ex: steroids, thyroid hormones, retinoids
• molecule-receptor complex = transcription factor
• binds to hormone response element (HRE): specific DNA sequence

Question 7

GPCR signaling process

Answer 7

• ligand binds to receptor, inducing conformational changes, allowing GPCR to interact and bind G protein
• receptor acts as GEF (exchanged GDP on alpha subunit for GTP, activating it)
• alpha subunit binds to effector molecule (activate or inhibit), which catalyzes rxns that produce 2nd molecule

Question 8

4 ways to cause signal desensitization

Answer 8

1. hormone lvl drop
2. remove signaling molecule
3. receptor sequestration (endosome)
4. receptor destruction (endosome + lysosome)

Question 9

Gs subunit: what ligand affects it and what does it do?

Answer 9

ligands: epinephrine and histamine
- stimulates adenylate cyclase
- activates PKA to phosphorylate target proteins and alter their activity

Question 10

Gi subunit: what ligands affect it and what does it do?

Answer 10

ligands: epinephrine/norepinephrine, dopamine
- inhibits adenylate cyclase
- no cAMP produced, PKA NOT activated

Question 11

Gt subunit: what ligands affect it and what does it do?

Answer 11

ligands: light
- stimulates cGMP phosphodiesterase
- how vision works

Question 12

Gq subunit: what ligands affect it and what does it do?

Answer 12

• ligands: acetylcholine
• activates phospholipase C
• PKC phosphorylates target proteins, activation of Calcium-calmodulin-dependent proteins

Question 13

Viagra and Caffeine effects on cAMP phosphodiesterase and cGMP phosphodiesterase

Answer 13

Viagra: inc. cellular cGMP lvls and prolong effects for longer time; smooth muscle relaxation and vasodilation (ERECTION

Caffeine: inhibit PDE, leading to cAMP accumulation, which increases heart rate

Question 14

Cholera and its effects on G proteins

Answer 14

• prevents Gs(alpha) inactivation
• G protein remains in active (GTP bound) state and continuously stimulates adenylate cyclase
• cAMP overproduction; opens Cl channels in intestinal cells –> loss of water and electrolytes (DIARRHEA)
• NaCl build up leads to osmotic gradient across membrane

Question 15

Pertussis toxin and its effect on G proteins

Answer 15

• prevents activation of Gi(alpha) subunit; prevents activation/dissociation from trimeric G protein complex
• cAMP overproduction; loss of fluids and excessive mucous secretion (Whooping Cough)

Question 16

Nitric Oxide and Smooth Muscle Relaxation

Answer 16

• diffuses to neighboring muscle and activates guanylate cyclase –> produces cGMP
• results in smooth muscle relaxation and vasodilation (LOWER BLOOD PRESSURE)
• patients taking nitrates should NOT take drugs that inhibit cGMP (erectile dysfunction drugs) –> EXTREME vasodilation and drops in blood pressure

Question 17

Antihistimines inhibit G protein-coupled receptor signaling

Answer 17

• used to treat allergies (block the effect of histamine)
• also able to cross Blood Brain Barrier (block neurotransmission)
• new drugs block blood brain barrier transmission (NON-DROWSY)

Question 18

Receptor Tyrosine Kinase (RTK) Signaling

Answer 18

• ligand binding causes dimerization, which phosphorylates tyrosine residues
• adaptor and docking proteins recognize phospho-tyrosines (RAS-dependent and independent paths)
• activate downstream signaling pathways –> alteration in gene transcription and protein activity

Question 19

RAS-dependent vs RAS-independent signaling facilitation

Answer 19

Dependent: mitogen-activated protein kinase (MAPK)
- Ras –> Raf –> Mek –> Erk –> affected proteins and gene

Independent: facilitated by different kinase

Question 20

Ras and cancer (mutant forms of Ras), neurofibromatosis

Answer 20

• mutations decrease GTPase activity and lock in active, GTP-bound state
• neurofibromatosis: tumor growth in nerve tissue
• caused by inactivation of neurofibromin gene (GAP for Ras) = Ras uncontrollably activated pathways for nerve tissue growth

Question 21

RTKs and cancer (Herceptin)

Answer 21

• excessive signaling from mutated/overexpressed RTKs associated w/cancer

RTK = pharmacological inhibitor target) –> Herceptin targets HER2 (breast cancer drug)