Cardiac / Vascular Signaling Flashcards
Describe the mechanisms by which PKA-mediated phosphorylation of L-type Ca2+ channels, ryanodine receptors, phospholamban, and troponin I affect inotropy and lusitropy.
PLB: normally slows down SERCA, but when phosphorylated it’s inhibited so SERCA takes up more. This increases lusitropy AND increases inotropy (SR spits out more Ca on next excitation)
RyR: Ca-stimulated Ca release channel. Phosphorylation makes it more sensitive, so it spits out more with less trigger. Increased inotropy
L-type Ca Chan: LTCC is on surface of PM. Phosphorylation slows inactivation, so it lets in more Ca which triggers more Ca released from SR (also increases inotropy)
TnI: decreases Ca sensitivtiy of TnC, so Ca can dissociate faster which increases lusitropy
Describe how HCN channels, L-type Ca2+ channels, and GIRK channels contribute to autonomic control of heart rate.
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Describe the differences between vascular smooth muscle cells and cardiac myocytes.
Not striated
No troponin
Contraction in VSMCs can be initiated by mechanical, electrical or chemical stimuli.
Slower contraction that can be sustained/tonic
Ca2+ release from the SR not essential for contraction in VSMCs. However, Ca2+ reuptake mechanisms are similar (SERCA & PLB)
- Describe the molecular steps involved in Ca2+ regulation of vascular smooth muscle contraction.
Ca2+ enters cytoplasm – from SR mainly, but also via voltage-gated Ca2+ channels on surface membrane.
Ca2+ binds to Calmodulin (CaM), a ubiquitous intracellular Ca2+ binding protein
Ca2+-CaM binds to Myosin Light Chain Kinase (MLCK) to activate it.
Activated MLCK phosphorylates the light chain of myosin (myosin head), which permits cross bridge cycling to occur.
Contraction halted by dephosphorylation of myosin light chain by Myosin Light Chain Phosphatase (MLCP).
Describe the mechanism by which sympathetic stimulation (via α1 adrenergic receptors) alters vascular tone.
a1 adrenergic receptors are GPCRs, which are coupled to the Gq G-protein.
Gaq activates PLC → DAG and IP3.
IP3 activates IP3Rs on SR of VSMCs.
IP3Rs are intracellular Ca2+ release channels.
Activation of IP3Rs ↑Ca2+ release from the SR.
↑Ca2+ →VSMC contraction and vasoconstriction.
PKC (a Ca2+ -dependent protein kinase) phosphorylates many targets in VSMCs, including L-type Ca2+ channels, which in turn activates additional intracellular Ca2+ release (CICR).
Describe the arterial baroreceptor reflex arc.
Arterial baroreceptor reflex arc: ↑blood pressure→↑baroreceptor firing rate→↓sympathetic output and ↑parasympathetic output from the cardiovascular center→↓heart rate, ↓inotropy and ↓vascular tone (vasodilation)→↓blood pressure.
The baroreceptor reflex is an acute short-term effect. Baroreceptors can adapt to prolonged changes in blood pressure by resetting to the new level over a time course of minutes to hours.
Name four tissue metabolites that control local flow to a capillary bed.
↓ PO2
↑PCO2/pH
↑K+: gets pumped out during skeletal muscle activity
↑Adenosine: Adenosine is used by hydrolysis of ATP. In VSMCs, adenosine binds to A2 purinergic receptors, which are GPCRs that are coupled to Gs, thereby ↑cAMP levels in VSMCs causing vasodilation by inhibition of MLCK.
Describe the myogenic response.
Feedback mechanism designed to maintain constant flow despite changes in pressure.
Totally intrinsic, no nerves
Stretch causes VSMC contraction by opening stretch-activated ion channels, which depolarize the VSMC, thereby ↑intracellular Ca2+ via L-type Ca2+ channels.
Describe how nitric oxide and endothelin regulate vascular smooth muscle tone.
In VSMCs, NO activates guanylate cyclase→↑cGMP.
cGMP activates PKG→↓intracellular Ca2+ via activation of SERCA and inhibition of L-type Ca2+ channels.
↓Ca2+ concentration causes relaxation of the VSMC (vasodilation).
Endothelin is a potent vasoconstrictor. It binds to ET receptors, GPCRs primarily coupled to Gq.
Endothelin response is similar to the a-adrenergic response, but the time course is different. Endothelin has both transient effects and longer lasting effects.
CDI of LTCC?
Calcium Dependent Inactivation of the L-Type Calcium Channel. If SR [Ca] is high, LTCC lets in less
If SR [Ca] is low, LTCC lets in more
Why do Timothy syndrome mutations of the L-type Ca2+ channel could result in a lengthened cardiac action potential
De novo mutations in CaV1.2 that SUPPRESS volt-dependent INACTIVATION –> long QT, AV block
One variant (TS) arises from the mutation G406R in exon 8a and another variant TS2 arises from two mutations (G402S and G406R) of exon 8 (which encodes the same region as exon 8a.
Why do Brugada syndrome mutations of the LTCC result in shortened action potentials.
These mutations cause a large reduction in the magnitude of L-type Ca2+ current which may be a consequence of impaired membrane trafficking.
These patients have significantly shortened Q-T intervals.
Know the mechanism whereby CPVT mutations, in combination with activation of β-adrenergic receptors, causes ectopic depolarizations.
Basically, the SR leaks out Ca. If it’s been stimulated by B-adrenergic, it leaks more Ca. The NCX gets rid of it, and you might depolarize the cell
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT): display abnormalities upon exercise or infusion of catecholamines.
Mutations in RyR2—with dominant inheritance—increase the resting “leak” of Ca2+ out of the SR and/or render RyR2 more sensitive to activation by Ca2+.
Homozygous mutations in the lumenal Ca2+ buffer calsequestrin2 (CasQ2)—with recessive inheritance—result in dramatic loss of luminal Ca2+ buffering
CPVT mutations + increased SR Ca2+ (increased as a consequence of activation of β-adrenergic receptors) is presumed to result in releases of Ca2+ that are not directly triggered by the L-type Ca2+ current during the plateau of the action potential but instead occur either shortly or long after repolarization.
Extrusion of the Ca2+ via NCX results in depolarizations that can trigger ectopic action potentials and thus initiate arrhythmias.
