Myocardial Transports and Protein Evolution

The Na+/K+ pump is composed of alpha and beta subunits. Alpha subunits are catalytic, while beta subunits are glycoproteins.

The Na+/K+ pump moves 3 sodium ions out and 2 potassium ions in for every ATP molecule used.

The pump exists in different shapes (E1 and E2). E1 has high affinity for ATP and low affinity for K+, while E2 has low affinity for ATP and high affinity for K+.

Directly measuring the pump activity using radioactive isotopes. This involves tracking ion movement with radioactive labels.

Measuring pump activity using ion-selective electrodes. This method measures the concentration of ions inside and outside the cell

Higher intracellular Na+ concentration leads to increased pump activity.

The ratio of ATP to ADP and Pi affects pump activity. ATP has a dual role, both in the catalytic process and as a regulator of the process

Changes in membrane potential influence the pump's activity. Depolarization increases Na+ efflux and decreases K+ influx.

Catecholamines increase cardiac pump activity through cAMP and PKA phosphorylation mechanisms.

Atrial natriuretic peptide (ANP) inhibits cardiac function.

Cardiac glycosides (e.g., digoxin, ouabain) inhibit the Na+/K+ pump, leading to increased intracellular Na+ and, indirectly, increased intracellular Ca2+ levels.

The Na+/K+ pump maintains Na+ and K+ gradients, membrane potential, and excitability in cardiac muscle cells and powers secondary active transport.

Phospholemman (PLM) regulates the Na+/K+ pump, influencing its activity via protein interactions and phosphorylation states.

Reduced Na+/K+ pump function or expression in heart failure leads to increased intracellular Na+, activating mitochondrial Na+/Ca2+-exchange which increases intracellular Ca2+ and damages ATP production.

Sodium-calcium exchanger (NCX) is a secondary transport mechanism that moves Na+ into the cell and Ca2+ out, important in regulating intracellular calcium levels.

The sodium-calcium exchanger (NCX) has alpha-subunits (1&2) for ion transport, 10 transmembrane segments, Calcium-binding domains, and operates via electrogenic transport.

Sodium-calcium exchanger (NCX) is a membrane protein that exchanges sodium ions (Na+) for calcium ions (Ca2+) across the cell membrane. It plays a crucial role in regulating intracellular calcium levels.

NCX operates by exchanging 3 Na+ ions for 1 Ca2+ ion. This can occur in two modes: Forward mode: Ca2+ out, Na+ in. Reverse mode: Ca2+ in, Na+ out.

Factors that affect NCX include: Membrane potential: Hyperpolarization favors reverse mode, while depolarization favors forward mode pH: Acidosis inhibits NCX, while alkalosis stimulates it.

NCX blockers are substances that inhibit the activity of the sodium-calcium exchanger. Some examples include: Ions: La3+, Cd2+, Ni2+ Organic compounds: amiloride, 2-4 dichlorobenzamil, KB-R 7943, SEA 0400, ORM-10103, ORM 10962

NCX plays a major role in removing calcium from the cell. It contributes to approximately 85% of calcium extrusion, while other mechanisms like the plasma membrane Ca2+ ATPase (PMCA) handle the remaining 15%.

NCX contributes to pacemaker activity by influencing the membrane potential of heart cells.

NCX plays a role in the relationship between heart muscle contraction strength and the rate of heartbeats.

NCX can contribute to arrhythmias (irregular heartbeats) in conditions like ischemia-reperfusion injury and calcium paradox. During these conditions, aberrant NCX activity can disrupt calcium homeostasis and lead to abnormal heart rhythms.

PMCA is a calcium pump that plays a crucial role in fine-tuning calcium extrusion during diastole (heart relaxation). It operates at a lower capacity compared to NCX but with a higher affinity for calcium.

E1 is a high-energy state with high affinity for calcium and is sensitive to ADP. E2 is a low-energy state with low affinity for calcium and is insensitive to ADP.

During systole (contraction), the rate-limiting step is the transition from E2 to E1. During diastole (relaxation), the rate-limiting step is calcium binding.

Magnesium ions are essential for SERCA's function. They help stabilize the protein and are required for ATP binding and hydrolysis.

Phospholamban is a regulatory protein that slows down SERCA's activity. It inhibits calcium uptake by the pump.

A protein found in cell membranes that transports sodium ions out of the cell and potassium ions into the cell using energy from ATP hydrolysis. It plays a crucial role in maintaining cell membrane potential and ion gradients.

The Na+/K+ pump consists of two main subunits: the alpha subunit, which is responsible for the catalytic activity, and the beta subunit, which is a glycoprotein that helps with the pump's stability and regulation.

The Na+/K+ pump moves 3 sodium ions out of the cell for every 2 potassium ions it moves into the cell.

The Na+/K+ pump operates in a cyclical process involving two main conformations (E1 and E2). E1 binds ATP and Sodium, and E2 binds Potassium. It utilizes energy from ATP hydrolysis to move sodium ions out and potassium ions into the cell.

Pump activity can be measured using various techniques. Direct flux measurements with radioactive isotopes can track ion movement, while ion-selective electrodes directly measure ion concentrations. Pump current measurements in voltage-clamped cells can analyze ion movement across the membrane.

Factors like intracellular sodium concentration, extracellular potassium concentration, ATP/ADP ratio, membrane potential, and the number of pumps influence the pump's activity. Increased intracellular Na+ stimulates the pump. High ATP levels increase activity, while low ATP levels decrease it. Depolarization increases Na+ efflux and decreases K+ influx.

The Na+/K+ pump maintains crucial sodium and potassium gradients across the cell membrane, contributes to the resting membrane potential, and powers secondary active transport systems that regulate calcium levels essential for muscle contraction.

In heart failure, reduced Na+/K+ pump function or expression leads to increased intracellular sodium, which triggers further damage and dysfunction in the heart muscle.

Drugs that inhibit the Na+/K+ pump, leading to increased intracellular sodium and indirectly, calcium levels.

Naturally occurring substances in the body that can act like cardiac glycosides, influencing heart function.

Ouabain, a cardiac glycoside, inhibits the Na+/K+ pump, leading to increased intracellular sodium and calcium, which can cause a heart abnormality known as 'delayed afterdepolarization.'

The Na+/K+ pump in heart muscle maintains ion gradients, membrane potential for excitability, and powers secondary active transport, particularly the sodium-calcium exchanger (NCX).

Phospholemman (PLM) interacts with and regulates the Na+/K+ pump. Its phosphorylation state influences pump activity.

A secondary active transport mechanism that exchanges sodium and calcium ions across the cell membrane, playing a key role in regulating intracellular calcium levels.

NCX can operate in two modes: Forward mode - moves calcium OUT, sodium IN. Reverse mode - moves calcium IN, sodium OUT.

The Plasma Membrane Calcium ATPase (PMCA) is responsible for fine-tuning calcium extrusion during diastole. It has a lower capacity but a higher affinity for calcium compared to NCX, playing a crucial role in maintaining calcium homeostasis.

SERCA (Sarco/Endoplasmic Reticulum Ca2+ ATPase) has three genes with alternative splicing, resulting in five isoforms.

The rate-limiting step in SERCA's function depends on the heart's state. During systole, it's the transition from E2 to E1. During diastole, it's calcium binding.

Phospholamban (PLB) is a regulatory protein that slows down SERCA activity, inhibiting calcium uptake. It's more influential in heart failure due to lower phosphorylation.

Sarcolipin (SLN) uncouples calcium transport from ATP degradation, leading to increased heat production.

The sodium-calcium exchanger (NCX) is a membrane protein that swaps sodium (Na+) ions for calcium (Ca2+) across the cell membrane, playing a crucial role in regulating intracellular calcium levels.

Key factors affect NCX activity: Membrane potential: Hyperpolarization favors reverse mode, while depolarization favors forward mode. pH: Acidosis inhibits NCX, while alkalosis stimulates it.

NCX is a major player in removing calcium from the cell, contributing to about 85% of calcium extrusion, while other mechanisms handle the remaining 15%.

NCX can contribute to arrhythmias (irregular heartbeats) in conditions like ischemia-reperfusion injury and calcium paradox, where abnormal NCX activity disrupts calcium homeostasis.

PMCA is a calcium pump with 10 transmembrane domains and a molecular weight of 140 kDa. It has binding sites for calcium and ATP, with a stoichiometry of 1 ATP : 1 Ca2+.

PMCA is involved in fine-tuning calcium extrusion during diastole (heart relaxation). It operates at a lower capacity than NCX but has a higher affinity for calcium.

PMCA is regulated by factors like calcium-calmodulin complex (which increases activity), protein kinase C (which stimulates via phosphorylation), and inhibition by the C-terminal region.