Signal Transduction

Question 1

What is a signal transduction pathway

Answer 1

• Chemical or physical signal transmitted through a cell as a series of molecular events
• Involved in regulating gene and protein activity
• Because cell membranes are only permeable to certain molecules, ligands bind extracellular domains which cause a change in the cytosolic domain and a cascade of events
• These ligands have the ability to alter protein function in the cytoplasm or protein synthesis in the nucleus, thus altering cytoplasmic machinery and cell behaviour
• Dysregulation can cause permanent damage or loss of activation pathways leading to cell cycle problems and uncontrolled growth

Question 2

What are the types of signal transduction pathways

Answer 2

• Receptor with protein kinase activity
• Receptor that interacts with a kinase
• Receptor that interacts with a G protein

Question 3

What are the characteristics of receptors with protein kinase activity

Answer 3

• Integral membrane proteins that span the membrane
• Consist of an N terminal (extracellular) and a C terminal (cytosolic)
• Single polypeptide dimers
• Cytosolic domain have protein kinase activity (ability to self phosphorylate)

Question 4

What is mechanism 1 of receptors with protein kinase activity

Answer 4

• Activated receptor activates enzyme (phospholipase / kinase)
• Leads to production of secondary messengers
• Inactive phospholipase C becomes activated and converts PIP2 to DAGand IP3
• This activates protein kinase C and mobilises Ca respectively

Question 5

What is mechanism 2 of receptors with protein kinase activity

Answer 5

• Activated receptor begins a cascade of events
• Signal is transmitted via several cytoplasmic kinases to phosphorylate a transcriptional regulator
• Activation of a kinase phosphorylates another kinase
• Cascade of activation to form a phosphorylated transcription factor
• Leads to translocation in the nucleus, binding DNA and subsequent effect on transcription

Question 6

What is EGF binding of receptors with protein kinase activity

Answer 6

• Takes into account mechanism 1 and 2
• It is a GF and thus bind EGF receptor
• This leads to auto-phosphorylation of a tyrosine kinase receptor
• This further activates PIP2, DAG and IP3 and subsequent deposition on the ER
• Activation of RAS-MAP kinase pathway leads to changes in gene expression

Question 7

What are the characteristics of receptors that interact with a kinase

Answer 7

• Receptor is not the kinase, but once activated can phosphorylate a kinase that elicits a cascade of events
• Involves JAK / STAT receptors
• JAK activation leads to activation of STAT and thus activation of GFs / STAT molecules (cell / tissue specific)

Question 8

What is the mechanism of receptors that interact with a kinase

Answer 8

• Receptor becomes activated through dimerisation (binding of ligand)
• JAK kinase that associates with inactive receptor becomes activated
• JAK kinases phosphorylates receptors on tyrosine
• Leads to phosphorylation of STAT (transcriptional regulator) and subsequent dissociation from receptor
• Formation of homo and heterodimers of STATs
• STATs translocate to nucleus, bind target site on DNA / gene regulatory proteins and affect transcription

Question 9

What are the characteristics of receptors that interact with a G protein

Answer 9

• Induced receptor interacts with globular G protein (3 subunits)
• Subunits are interchangeable and can elicit number of cascades
• Must be tightly regulated and controlled
• Causes GDP from alpha subunit to be replaced by GTP

Question 10

How does protein kinase A aid interactions with a G protein

Answer 10

• Regulatory tetramer
• Two catalytic and two regulatory subunits
• Contain cAMP binding site
• Inactive messenger

Question 11

How does cAMP act as a receptor that interacts with a G protein

Answer 11

• cAMP binds regulatory subunits of protein kinase A
• cAMP binding releases catalytic subunits
• Free catalytic subunits can enter nucleus and phosphorylate CREB (cAMP response element binding protein)
• CREB binds at cAMP responsive element of DNA
• Recruits RNA pol II and activates downstream transcription of genes

Question 12

How do postsynaptic receptors act as a receptor that interacts with a G protein

Answer 12

• Metabotropic
• Neurotransmitter binds receptor that is coupled to G protein
• Leads to dissociation of subunits and subsequent activation of effector protein
• Effector protein modulates ion channels directly and indirectly via intracellular effector enzymes / second messengers
• Dependent on receptor, produces either excitatory or inhibitory postsynaptic potential

Question 13

What is short term sensitisation (serotonin)

Answer 13

• Serotonin (neurotransmitter) binds G protein coupled receptors
• Production of cAMP from ATP
• cAMP binds regulatory unit of protein kinase A causing dissociation of catalytic subunits
• Catalytic subunits phosphorylate and close K channels, reduce outflow
• Prolongs AP, opening Ca channels (increase influx)
• Increase Glu release across synaptic cleft

Question 14

What is long term sensitisation (serotonin)

Answer 14

• Continual release of serotonin binds G protein coupled receptors
• Prolonged serotonin induced enhancement of Glu release
• Catalytic subunits influence phosphorylation of CREB
• Changes in gene expression involved in differentiation (GFs, Glu neuronal growth / differentiation)
• Leads to long-term increase in number of synapses between sensory and motor neurons (molecular basis of learning)