regulation Flashcards
Regulation of the CV system involves
coordinated control of the heart and vasculature
GPCRs are
7-transmembrane- spanning (7TM) integral membrane proteins that transduce ligand binding to intracellular signaling.
A few cardiovascular GPCRs include:
- α & β adrenergic receptors,
- acetylcholine receptors,
- endothelin receptors,
- adenosine receptors,
- angiotensin II receptors.
GPCR activation:
- agonist binds receptor,
- GTP replaces GDP on α subunit of heterotrimeric
- G protein causing dissociation of α and βγ G protein subunits.
- Both α and βγ can be active signals.
GPCR deactivation:
auto dephosphorylation of GTP to GDP by α subunit permits reassociation with βγ. Rebinding of G protein to receptor causes inactivation.
Families of G proteins involved in cardiovascular function:
Gs, Gi/o, Gq.
Gs and Gi/o are
stimulatory & inhibitory, respectively, for cAMP production by adenylate
cyclase.
Gq activation
increases intracellular Ca2+ via activation of phospholipase C (PLC) and
Protein Kinase C (PKC).
b blockers are used to treat
arrhythmias, hypertension, and for cardioprotection post-MI
angiotensin II receptor blockers
used to treat
hypertension and heart failure
PKA is
- cAMP dependent protein kinase
- has 2 regulatory and 2 catalytic subunits
- binding of 4 cAMP molecules causes dissociation
- free catalytic subunit can phosphorylate target proteins
α1 adrenergic: G proteins
Gq
β adrenergic: G protein
Gs
β1 and β2
muscarinic Ach: G protein
Gi/o
α1 adrenergic: signaling pathway
PLC, PKC → increases intracellular Ca2+
β adrenergic: signaling pathway
- stimulates adenylate cyclase
2. increases cAMP
muscarinic Ach: signaling pathway
- inhibits adenylate cyclase
- decreases cAMP
- releases βγ subunits
α1 adrenergic: effects
vasoconstriction
β adrenergic: effects
- heart: increase chronotropy, inotropy, lusitropy, dromotropy
- vascular beds in skeletal muscle: vasodilation
muscarinic Ach: effects
decrease chronotropy
autonomic regulation of inotrophy can be
- sympathetic regulation of inotrophy
2. parasympathetic regulaiton of inotropy
sympathetic regulation of inotrophy can be through
- cAMP signaling
2. molecular targets for sympathetic regulation of inotropy and lusitropy
molecular targets for sympathetic regulation of inotropy and lusitropy can be through
- phospholamban (PLB)
- L-type Ca2+ channels (LTCCs)
- Ryanodine Receptors (RyRs)
- Troponin I (TnI)
cAMP signaling
- Sympathetic neurons innervate the heart, release NE,
- NE binds to β adrenergic receptors to increase cAMP.
- Phosphodiesterases breaks down cAMP (and cGMP) and help to establish intracellular signaling microdomains and specificity of signaling
- PKA
PKA is
- cAMP-dependent protein kinase.
- Major effector for cAMP signaling in heart.
- Phosphorylates target proteins (counterpart = phosphatases that dephosphorylate targets).
- Phosphorylation changes protein function by changing conformation and charge.
Gs functions
- stimulatory G protein
- activates adenylate cyclase
- increases cAMP
- activated PKA
Gi/o functions
- inhibitory G protein
- inhibits adenylate cyclase
- decreases cAMP
- inhibits PKA
Gq functions
- quirky G protein
- activated PLC
- activated PKC
- increases Ca2+
(via IP3R activation and SR Ca2+ release)
Sympathetic stimulation increases inotropy via
PKA phosphorylation of at least 4 proteins involved in EC coupling.
