L22 - calcium signalling intro Flashcards
(28 cards)
what is blood pressure
the pressure of blood on the walls of the blood vessels as our heart pumps blood around the body
a force
what are the determinants of blood pressure
blood volume
cardiac output
peripheral vascular resistance
how does vasoconstriction and vasodilation impact blood pressure
constriction of the peripheral blood vessel will increase BP because of increased pressure being placed on the blood. alternatively dilation reduces BP
what signals changes in vessel diameter
Biochemical signals:
response to biochemical (Ang II,
noradrenaline, ET-1 etc) –> increases calcium
Biomechanical: (flow/shear stress)
stimuli –> blocks the action of ca+
what are the two cell types involved in the regulation of VSM
VSMC and Endothelial cells
describe the contraction of vascular smooth muscle cells
- ↑[Ca2+ I → Ca2+ -calmodulin (CaM)-
dependent activation of myosin light chain kinase (MLCK) - MLCK phosphorylates the myosin regulatory light chain (RLC20)
- Initiate actin-myosin cross-bridge formation → Contraction
describe the relaxation of VSMC
- GPCR-mediated pathway activates RhoA dependent kinase (ROCK)
- ROCK activation of myosin light chain
phosphatase (MLCP) - Dephosphorylates MLC → Relaxation
what’s the concentration difference between extracellular and cytosolic ca+
Extracellular = 1-2mM, Cytosolic= 100nM
what are the 6 ways calcium enters the cytosol
- Voltage-operated channels (VOCs)
- Receptor-operated channels
- Store-operated calcium entry (SOCE)
- Purinergic receptors
- Transient receptor membrane potential (TRP) channels
- Na+/Ca2+ exchanger
what are the three families of voltage calcium channels
Cav1, Cav2, Cav3
what determines a channel’s gating properties
the amino acid sequence of the large pore-forming α1 subunit determines
the gating properties and sensitivity to Ca2+ channel blocker
what are the various roles of the TM domains in VOCC
TM5-6: forms channel pore
TM4: positively charged; rotates and open the channel in response to
depolarisation
TM6: lines the inner pore; binding site for phenylalkylamines and dihydropyridines
what are the two types of VOCCs
Transient (T-type) and Long-lasting (L-type)
what differentiates L and T-type VOCCs
T-type: consist of primarily Cav3 subunits
L-type: consist of primarily Cav1 subunits
- T-type: activate at -60mV and peak at -15mV
- L-type: activate at -30mV and peak at +30mV
Regulation of VSMC contractility by VOCCs
- Ca2+ entry via L-type (Cav1.2) and T-type (Cav3.1) channel → VSMC contraction
- Cav3.2 activates ryanodine receptors → Ca2+ release from SR → activates Ca2+-activated K+ channel → hyperpolarisation → inhibits Cav1.2 and Cav3.1
Receptor-operated Ca2+ channels (ROCCs)
- Ligand binding to GPCR or TKR
- Activates phospholipase C → ↑ IP3 (SOCE) and DAG (Primary)
- Release of intracellular Ca2+ storage and opening of Transient
receptor membrane potential (TRP) channels - ↑ intracellular Ca2+ level
- VSMC contraction
Store-operated calcium entry (SOCE) mediated contraction
- IP3 activates IP3 receptor
on SR (IP3 from ROCC) - Ca2+ release from storage
- ↑ intracellular Ca2+ level
- VSCM contraction
REUPTAKE - Ca2+ uptake by Sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) back into the SR
- Maintains low cytosolic Ca2+ conc.
Store-operated calcium entry (SOCE) mediated relaxation
Relaxation
1. Ca2+ release from endolysosome via
TRPML1 channel or Ca2+ entry through TRPV4 channel
2. Activates ryanodine receptors (RyRs) → Ca2+ release
3. Ca2+ activate BKCa channels.
4. Hyperpolarize the membrane and vasodilation
which of the three Inositol trisphosphate receptors (IP3Rs) are found in VSMC
IP3R1 and IP3R3
activation of Inositol trisphosphate receptors (IP3Rs)
IP3Rs activation requires binding of IP3 to all four of its subunits and Ca2+ binding
(at low concentrations Ca+ is a pure agonist)
Ca+ inactivation of IP3Rs
as increasing amounts of calcium pass through IP3R concentrations over 300nm will cause them to close only in the presence of IP3 will they reopen
Ca2+-induced Ca2+ release (CICR)
- Mediated by ryanodine receptors (RyRs) on SR
- ca+ binding to RyRs causes intracellular calcium to be released into the cytoplasm
- each RyR isoform 1-3 have been identified in VSMC
- the probability teh an RyR channel is open is concentration dependent on how much calcium is present
what is calcium spark
a localised release of ca+ caused by RyR causes vasodilation
how does a calcium spark occur
when a small cluster if RyR channels (4-6) release calcium in a localised area in which BKCa are present
BKCa are calcium activated potassium channels in the presence of high levels of calcium –> causes an efflux of K+ and hyperpolarization of the membrane inhibiting L-type Ca+ channels –> vasodilation
