Cardio basic physiology: ions and channels Flashcards
What is phospholamban (PLB)?
PHOSPHOLAMBAN (PLB) is phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca2+-ATPase (SERCA2a) activity and cardiac contractility.
what does dephosphorylated PLB do?
inhibits SERCA2a, ie PLB is ACTIVE
what happens when PLB is phosphorylated?
inhibition of SERCA2a is reversed , ie PLB is INACTIVATED
what does SERCA2a do?
it controls the rate of cytosolic Ca2+ removal and the degree of SR Ca2+ load»_space; determines the cardiac relaxation and contraction
what is the relaxation mechanism in a cardiomyocyte?
When Ca rises above resting levels, ATP-dependent Ca pumps in the SR Ca-ATPase, SERCA, are activated and start to pump Ca from the cytosol back into the SR.
As the AP repolarises and L-type ca channels inactivate, this mechanism reduces [Ca] towards resting levels, so Ca dissociates from troponin C and the muscle relaxes.
The Ca originally entering the cell is expelled by the Na-Ca exchanger (NCX) in the membrane. This uses the inward electrochemical Na gradient to pump 1Ca out and 3Na in.
At the end about 80% of the Ca is rezequesrtered into the SR, most of the rest is ejected from the cell.
what is major characteristic in human and experimental heart failure?
depressed SR Ca2+ uptake associated with decreased SERCA2a levels and dephosphorylation of PLB»_space;> decreased Ca2+ load and impaired contractility
how is PLB phosphorylated?
In vitro, PLB can be phosphorylated at three sites:
SEr16 by cAMP- and cGMP-dependent protein kinases,
Thr17 by CaMKII and
Ser16 by protein kinase C
• Phosphorylation of Ser16 and Thr 17 by PKA and CaMKII has been shown to mediate what effects of Beta1AR stimulation?
the positive inotropic and relaxant effects of Beta1-adrenergic stiulation in the heart
How is PLB dephosphorylated?
by a SR-associated type 1 phosphatase (PP1).
what is HS-1 associated protein X-1 (HAX-1) and what does it do with PLB?
• PLB can be regulated by the HS-1 associated protein X-1 (HAX-1), which is ubiquitously expressed in mitochondria and SR.
o HAX-1 increases PLB inhibition of SE Ca2+ cycling and contractility, whereas Beta1-adrenergic stimulation relieves this inhibition.
• Hsp20 is what?
• Hsp20 is an interacting partener of PP1 and inhibitor of its enzymatic activity» prevents PLB dephosphorylation»_space; resulting in diminished PLB inhibition and enhanced cardiac function.
How is protein phosphatase 1 (PP1) regulated?
Inhibited by Hsp20 and inhibitor-1 (I-1)
In short, what happens when PKA phosphorylates phospholamban?
• PKA phosphorylates phospholamban, reducing its inhibitory effect on the Ca-ATPase pump of the SR. this disinhibition increases the Ca affinity of the pump and boosts Ca transfer from sarcoplasm into SR. this accounts for most of the lusitropic effect. Beta-AR stimulation may also phosphorylate the Ca release channel (RyR, so that a bigger fraction of the raised Ca store is released per excitation.
