Cardiac Signaling

Question 1

Molecular targets of PKA (4)

Answer 1

1. LTTCs
2. Phospholamban
3. RyR
4. Tn-I

Question 2

Regulation of Phospholamban by PKA

Answer 2

PLB binds SERCA, inhibiting it; phosphorylation of PLB by PKA causes it to dissociate from SERCA, releasing its inhibition and increasing Ca2+ reuptake

Increased Ca2+ reuptake increases inotropy & lusitropy

Question 3

Regulation of LTTCs by PKA

Answer 3

Phosphorylation of LTTCs by PKA slows inactivation, thereby increasing L-type Ca2+ trigger current; this increases inotropy

Question 4

Regulation of RyR by PKA

Answer 4

Phosphorylation of RyRs by PKA makes them more sensitive to Ca2+ so that less trigger Ca2+ is needed to evoke CICR; this increases inotropy

Question 5

Regulation of TnI by PKA

Answer 5

Phosphorylation of TnI by PKA decreases its Ca2+ sensitivity, causing faster dissociation of Ca2+ from the troponin complex; this increases lusitropy

Question 6

Parasympathetic signaling via M2

Answer 6

ACh from parasympathetic fibers binds the M2 muscarinic receptor, which is coupled to Gi protein; activated Gi-By binds to GIRK channels, activating the IKACh current

Activated Gi-alpha protein inhibits adenylate cyclase leading to reduced activity of PKA; this is a secondary mechanism of parasympathetic control

Question 7

G-protein inwardly-rectifying K+ (GIRK) channel

Answer 7

Conducts the outward K+ (IKACh) current which stabilizes the membrane potential near EK; acts to dampen excitation and slow spontaneous firing frequency

Activated by the Gi-By protein via parasympathetic control

Question 8

Vascular smooth muscle contraction

Answer 8

Graded depolarization activates membrane LTCC allowing influx of trigger Ca2+ which activates Ca2+ release from the SR; Ca2+ binds CaM and Ca2+-CaM binds to MLCK, activating it; MLCK phosphorylates the myosin head, permitting cross-bridging to occur

Question 9

Vascular smooth muscle relaxation

Answer 9

Myosin light chain phosphatase (MLCP) de-phosphorylates myosin heads, causing relaxation

PKA can also phosphorylate MLCK, inhibiting it and reducing VSMC contraction

Question 10

alpha 1 adrenergic signaling

Answer 10

Sympathetic neurons release NE onto alpha-1 adrenergic receptors, which are coupled to Gq protein; Gq protein activates PLC which produces DAG and IP3

IP3 activates IP3Rs on the SR of VSMCs, causing Ca2 release into the sarcoplasm and resulting in VSMC constriction

Ca2+ also activates PKC, which phosphorylates LTCCs, increasing inward Ca2+ current and leading to greater Ca2+ release via CICR

Question 11

Arterial baroreceptor reflex art

Answer 11

Pressure-sensitive neurons in the aortic arch and carotid sinus project to the cardiovascular control center in the medulla via CN IX; the CV control center projects efferent sympathetic and parasympathetic fibers to the heart and vasculature

Question 12

eNac

Answer 12

Mechanosensitive Na+ channels located in baroreceptor cell membranes

Question 13

Low pressure baroreceptors

Answer 13

Located in the atria and vena cavae; respond to changes in venous pressure by changing firing rate; efferents project to SA node to control HR

Question 14

Bainbridge reflex

Answer 14

Stretching of low pressure baroreceptors in the atria and vena cavae causes sympathetic projection to the SA node, increasing chronotropy

Question 15

Peripheral chemoreceptors

Answer 15

Found in aortic and carotid bodies, near the aortic arch; respond to changes in PO2/PCO2

Ex: Low PO2/High CO2 results in increased sympathetic output, sparing O2 delivery to the heart and brain

Question 16

Vasoactive metabolites (4)

Answer 16

Produced by increased muscle metabolic activity:

1. Decreased PO2
2. Increased PCO2/decreased pH
3. Increased extracellular K+ - results from inability of Na/K pump to keep up
4. Increased adenosine - produced by hydrolysis of ATP

Question 17

Adenosine signalign in VSMCs

Answer 17

Adenosine binds to A2 purinergic receptors, which are GPCRs coupled to Gs; Gs activates adenylate cyclase and increases cAMP in VSMCs; this activates PKA which phosphorylates MLCK, inhibiting it and causing vasodilation

Question 18

Myogenic response

Answer 18

Feedback mechanism to maintain constant flow despite changes in pressure

Stretch causes opening of stretch-activated Ca2+ channels of the Trp family; inward Ca2+ current directly causes vasoconstriction and also depolarizes the VSMC, further increasing intracellular Ca2+ via LTCCs

Question 19

NO signaling

Answer 19

NO is produced in the endothelial cells and diffuses into VSMCs; there, it activates guanylate cyclase, which produces cGMP; cGMP activates PKG which phosphorylates, thereby activating, SERCA; this reduces intracellular CA2+

PKG also inhibits LTCCs leading to decreased Ca2+ influx

Decreased Ca2+ causes VSMC relaxation (vasodilation) via reduced activity of MLCK

Question 20

Production of NO

Answer 20

Parasympathetic release of ACh onto the endothelial membrane activates Gq; the resulting increase in intracellular Ca2+ activates NOS in vascular endothelial cells to produce NO from L-arginine and O2

Question 21

Atrial Natriuretic Peptide (ANP) signaling

Answer 21

ANP is a vasodilator peptide released by the atria in response to mechanical stretching; ANP acts on natriuretic peptide receptors (NPRs) which are receptor guanylate cyclases that produce cGMP; cGMP activates SERCA to stimulates Ca2+ uptake, thereby reducing cytoplasmic Ca2+ levels and causing vasodilation, diuresis, and inhibition of aldosterone & renin release