Midterm 2 Flashcards
what occurs in the latch state of vascular smooth muscle contraction (caused by tonic stimulation)?
- sustained stimulation maintains modest increases in Ca2+ required for sustained tension
- Ca2+ leads to low levels of MLCK activation (cross-bridges already formed)
- MLCP dephosphorylates a portion of myosin molecules
- dephosphorylated myosin has a low rate of detachment from actin
- slow cross-bridge detachment maintains tension with lower ATP use
why is development of force is VSM slow?
- it doesn’t need to be fast
- requires a slow, sustained contraction
- VSM must sustain vasoconstriction for min-hours
what are the characteristics of the force-velocity relationship of VSM?
- slow velocity of shortening
- high force generation
- a large range of length due to “side polar” myosin thick filaments (different isoform)
how does smooth muscle shortening velocity increase?
increases with fraction of MLC that is phosphorylated
- increased calcium binds more calmodulin (Ca-CaM)
- activates more MLCK, more MLC phosphorylated
- leads to increased shortening velocity and maximum force (velocity and force dictated by MLCK activity)
how are store-operated channels (SOCs) involved in Ca2+ regulation?
ex) Orai in plasma membrane of VSM
- connects to STIM (SR Ca2+ sensor on SR)
- STIM detects low levels of Ca2+ in SR, allowing Orai to allow Ca2+ from extracellular space to directly enter SR
how are receptor-operated channels (ROCs) involved in Ca2+ regulation?
- second-messenger activated (ex. GPCR - Gq)
- often non-selective cation channels; can work in 2 ways:
- can open directly and allow Ca2+ influx
- can open allowing cation influx, depolarizing the membrane and open Cav1.2 channels
what is Istretch and how does it contribute to Ca2+ regulation?
- Istretch is stretch-activated; enters through K+ channels or non-selective ion channel
- can directly allow Ca2+ influx or depolarize the membrane and open Cav1.2 channels
how is Ca2+ released from the SR?
- through RYR3 channels activated by Ca2+ binding (CICR - not a big factor in VSM)
- through IP3R channels activated by IP3 binding (greater factor)
which SERCA isoform is present in VSM?
SERCA2b (SERCA2a in cardiac muscle)
- much slower
in the Ca2+ vs time graph during VSM contraction, what mechanisms are responsible for the transient Ca2+ peak and the sustained Ca2+ plateau?
transient Ca2+ peak:
- SR Ca2+ release
sustained Ca2+ plateau:
- Ca2+ entry via ROCs, SOCs, and Cav1.2
in the Ca2+ vs time graph during VSM contraction, what mechanisms are responsible for the clearance of cytosolic Ca2+? what are their properties?
- NCX (3Na in, 1Ca out): causes final fall; low affinity, high capacity (no ATP required)
- PMCA (1Ca out for every ATP): causes initial fall; high affinity, low capacity
- SERCA: causes initial fall; high affinity, low capacity
low capacity because they require ATP
where does the IP3 that is required to activate IP3Rs come from?
ex) SNS activation
- NE binds a1-adrenergic receptors, activating Gq
- Gq activates PLC which converts PIP2 (in the membrane) to inositol triphosphate (IP3) and diacylglycerol (DAG)
- IP3 activates IP3R on SR, increasing SR Ca2+ release
how does DAG contribute to VSM regulation?
- activates PKC which inhibits MLCP
- inhibited MLCP increased Ca2+ sensitivity of VSM contraction
- increases cross-bridge formation and force of contraction -> vasoconstriction
in summary, what are the transporters involved in Ca2+ regulation in the sarcolemma?
Ca2+ entry:
- Cav1.2
- ROCs
- SOCs
- stretch-activated cation channel
extracellular efflux:
- NCX
- PMCA
in summary, what are the transporters involved in Ca2+ regulation in the sarcoplasmic reticulum?
- SR Ca2+ release channels: RYR3 and IP3
- SR Ca2+ uptake by SERCA and PLB
what are the dominating mechanisms in each type of muscle for excitation-contraction coupling?
- skeletal: voltage-dependent Ca2+ release (VDCR)
- cardiac: calcium induced calcium release (CICR)
- smooth: IP3-induced calcium release (IP3ICR)
what is VDCR?
- physical coupling of Ca channel and RYR
- depolarization required for RYR Ca2+ release but Ca2+ entry not necessary
what is CICR?
- Ca2+ entry through Cav1.2 is an absolute requirement
- Cav1.2 is in close proximity with RYR
- triggers RYR Ca2+ release from SR
what is IP3ICR?
- Cav1.2 and RYR not in close opposition (little CICR)
- binding of IP3 to SR IP3 receptors triggers Ca2+ release (RYR causing some CICR)
- role for Ca2+ entry pathways across sarcolemma
what are the different types of VSM regulation?
1) frequency dependent (eg. GI tract)
- summation
- AP upstroke initiated by Cav1.2
2) slowly depolarizing waves (eg. uterus)
- oscillating membrane potential
3) tonic depolarization induced waves, no APs (eg. multi-unit SMCs)
4) pharmacomechanical coupling
- force generation w/o depolarization
- most common and diverse stimulation of VSM
what ways are there to depolarize the membrane?
- pacemaker channels (gut)
- inhibition of Na/K-ATPase (slower depolarization)
- changes in K+ channel
- non-selective cation channels
what mediators and second messengers are involved in pharmacomechanical coupling?
- mediators: drugs, hormones, NTs, local environmental changes
- second messengers altering Ca2+: IP3, cGMP, cAMP
how is VSM neurally regulated?
at the varicosity of a sympathetic axon synapsing onto a VSM cell, neural force generation occurs from fastest to slowest by the following mechanisms:
1) ATP (binds to non-selective cation channel (P2x receptor) causing Ca2+ and Na+ influx)
2) norepinephrine (binds to a1-adrenergic receptor, Gq activation, PLC, IP3, IP3R, SR Ca2+ release)
3) neuropeptide Y (binds Y1 receptor, increases intracellular Ca2+)
what factors are involved in endothelial regulation of VSM contraction?
- endothelium-derived relaxation factor (EDRF)
- now known to be nitric oxide (NO)
- endothelin (ET)
- endothelium-derived hyperpolarizing factor (EDHF)