Part Four: Second Messengers Flashcards
Second messengers
are small intracellular molecules that transmit and amplify the initial signal from the ligand activated receptor
ideal properties: Rapid generation, small size and ability to readily diffuse, rapid removal from system
Classifications
Ions,
Water soluble molecules
membrane associated molecules
Calcium 2nd messenger
used by cells to regulate many diverse activities:muscle contraction, secretion, metabolism, neuronal excitability etc
- simply moved around cell, not made nor destroyed
- {Ca] in the particular compartment of the cell is the signal detected by the next member in the signaling cascade
[Ca] high vs low
cell activation depends on the balance bw calcium-off and calcium-on mechansims
low cytoplasmic [Ca] (10^-7M) - cells remain quiescent
Increases in [Ca ] - sensors detect rise and activate specific response
Ca removal (off mechanisms
-pump Ca from cell or back into internal stores (hindered by large electrochemical gradient)
-Plasma membrane protein Ca pumps: Na-Ca exchanger (NCX) antiporter (low affinity, high transport rate)
Ca-ATPase (PMCA) (high affinity, low transport rate)
-Intracellular Ca pumps: Sarco/endoplasmic reticulum Ca-ATPase (SERCA)
Calcium addition (on mechanisms)
add from extracellular sources and internal stores–favored by large electrochem gradient
- Plasma membrane channels:
- Ligand gated ion channel receptors (ccation selective) - nerve/smooth muscle
- Voltage Gated channels–AP responsive, nerve, muscle, some endocrine
Intracellular calcium channels:
1,4,5-Inositol triphosphate receptors (IP3R)-universal
Ryanodine receptors (RyR)- skeletal and cardiac
(both are CALCIUM induced CALCIUM release)
Calcium molecular sensors (action)
Calcium binding proteins act as molecular sensors to detect changes in Ca concentration
-Activated sensors stimulate the cascade of downstream proteins to regulate specific functions
-2 major sensors: Tropinin C and Calmodulin
Tropinin C
TnC
is restricted to skeletal and cardiac muscle
-regulate contraction by controlling actin-myosin interactin
Calmodulin
CaM found in all cells mediates many regulatory pathways -Serine/threonine kinases -phosphatases -PMCA pumps -Adenylate cyclases
Ca-CaM dependent protein Kinase
CaM Kinase II
- Ca binds to CaM, making complex,
- this complex binds to inhibitory domain at C terminal of inactive protein
- becomes activated,
- ATP autophosphorylation makes new complex fully active, Ca-CaM complex dissociates
- leaves 50-80% active, then phosphatase inactivates it by removing phosphate
Cyclic nucleotides
cAMP
cGMP
cAMP cytoplasmic source
Adenosine Triphosphate
cAMP effector enzyme
adenylate cyclase at plasma membrane, removes pyrophosphate from ATP
cAMP enzyme activation
G protein coupled receptors (alpha and beta-gamma subunits)
cAMP function
activators of PKA
cAMP control
regulation of cell metabolism
long lasting changes in gene expression (metabolic enzymes, polypeptide hormones, ion transport proteins)
cAMP action
ligand binds to G protein and sends alpha subunit w/ bound GTP binds to adenylate cyclase, which w/ ATP produces cAMP, which binds to receptors
Regulation: Depending on which G protein is activated can gave +/- effect
Cholera toxin
increases PKA activation
sustained opening of Cl channels
excessive loss of water and Na into intestine (dehydration and shock)
Pertussis toxin
Increased PKA activation
altered hormonal activities
HIgh insulin; low glucose (seizures)
High histamine; low pressure (shock)
cAMP termination
cAMP phosphodiesterase w/ h20 makes 5’-AMP
cGMP cytoplasmic source
GTP
cGMP effector enzyme
soluble guanylate cyclase-generates cGMP from GTP
membrane associated guanylate cyclase (when NO is present)
cGMP enzyme activation
gaseous NO
enzyme linked receptors
cGMP function
activator of cGMP-dependent kinase (PKG) and cGMP dependent phosphodiesterase
Regulator of cGMPgated ion channels
cGMP control
regulation of muscle and nonmuscle contractility, visual signalling, blood volume homeostasis
cGMP action
both effector enzymes bind GTP, and produce cGMP, which activates PKG phosph of enzymes
cGMP termination
cGMP Phosphodiesterase w/ h2o creates 5’GMP
Phospholipid derivatives
membrane sources
-PI (phosphotidylinositol), PIP (phosphotidylinositol-4-phosphates), PIP2 phosphotidylinositol-4,5-bisphosphates)
-PC-phosphatidylcholine
PE-phosphatidylethanolamine
Phospholipid derivatives
IP3-1,4,4 inositol trisphosphate
DAG- diaglycerol
AA- arachidonic acid
PIP3- phosphatidylinositol-3,4,5 trisphosphate
