CVPR 03-26-14 08-10am Regulation of the CV system - Proenza Flashcards
G Protein-Coupled Receptors (GPCRs) – defn.
7-transmembrane-spanning (7TM) integral membrane proteins that transduce ligand binding to intracellular signaling; some of the most prevalent drug targets (beta blockers, angiotensin II blockers)
Cardiovascular GPCRs include…
α & β adrenergic receptors, ACh receptors, endothelin receptors, adenosine receptors, angiotensin II receptors.
GPCR activation scheme
Agonist binds receptor –> GTP replaces GDP on α subunit of heterotrimeric G protein –> 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 and Gi/o proteins
Gs & Gi/o are stimulatory & inhibitory, respectively, for cAMP production by adenylate cyclase
Gq protein
Its activation increases intracellular Ca2+ via activation of phospholipase C (PLC) and Protein Kinase C (PKC)
α1 adrenergic receptor - G protein, signaling pathway, effects
Gq —- Pathway: PLC, PKC –> increases intracellular Ca2+ —> vasoconstriction
β adrenergic receptor - G protein, signaling pathway, effects
Gs (β1 and β2)— Pathway: Simulates adenylate cyclase, increases cAMP —> In heart, increases chronotropy, inotropy, lusitropy, dromotropy…..In skeletal muscle vascular beds, vasodilation.
Muscarinic receptor - G protein, signaling pathway, effects
Gi/o —- Pathway: Inhibits adenylate cyclase –> decreases cAMP; Releases βγ subunits….. Effect: Decreased chronotropy
Regulation of Inotropy
Autonomic; both sympathetic & parasympathetic
Sympathetic regulation of inotropy
cAMP signaling, Phospholamban (PLB), phosphorylation of L-type Ca2+ channels & RyRs by PKA, phosphorylation of TN-I
Process to Increase of cAMP
Sympathetic neurons innervate the heart, release norepinephrine –> binds β adrenergic receptors to increase cAMP
Phosphodiesterases - what it is & action
= counterpart to adenylate cyclase; Breakdown cAMP (and cGMP) —> help to establish intracellular signaling microdomains and specificity of signaling
Protein Kinase A (PKA) - what it is & action
cAMP-dependent protein kinase; Major effector for cAMP signaling in heart; Phosphorylates target proteins (its counterpart is phosphatases that dephosphorylate these targets) —> changes protein function by changing conformation & charge.
Phospholamban (PLB)
PLB is an inhibitor of SERCA (which removes Ca2+ from cytosol following contraction by pumping it back into the SR)
Un-inhibiting SERCA
Phosphorylation of PLB by PKA causes it to dissociate from SERCA, thereby relieving the inhibition and increasing Ca2+ reuptake rate.
Two effects of Faster Ca2+ reuptake has on cardiac performance:
1) directly increases “lusitropy” (relaxability) – and 2) increases inotropy by increasing SR Ca2+ load.
Lusitropy
the ability of the heart to relax
Inotropy
Alteration of the the force or energy of muscular contractions….Negatively inotropic agents weaken the force of muscular contractions, while Positively inotropic agents increase the strength of muscular contraction
L-type Ca2+ channels (LTCCs) - action
On the plasma membrane; Activated by depolarization —> influx of Ca2+ —> triggers larger Ca2+ release from SR via ryanodine receptors (Ca2+-induced Ca2+ release (CICR))
PKA & L-type Ca2+ channels
Phosphorylation of L-type Ca2+ channels
by PKA slows inactivation –> increases magnitude of L-type Ca2+ current —> this increase in “trigger Ca2+” elicits a larger release of Ca2+ from the SR, thereby increasing inotropy.
Troponin I (TnI) - action
The inhibitory unit of the troponin complex (TnC-TnI-TnT); Along w/tropomyosin, inhibits the interaction btwn actin & myosin in the absence of Ca2+.
Phosphorylation of Troponin I (TnI)
TnI is phosphorylated by multiple kinases, including PKA…..Phosphorylation of TnI decreases the Ca2+ sensitivity of TnC —> would expect to decrease inotropy (counter to the sympathetic effect), BUT it rather results in faster dissociation of Ca2+ from TnC, thereby increasing lusitropy, which allows the heart to fill more quickly (increases lusitropy; no effect on inotropy?). This is particularly important at higher heart rates.
Parasympathetic regulation of inotropy
Parasympathetic innervation of the ventricle is sparse, thus there is little parasympathetic control of inotropy.