The Wonders Of Adrenalin Rushes, aka β-adrenergic Agonist Effects On The Heart

For a long time, I've been fascinated, on a personal level, with what occurs mechanistically during an adrenalin rush. For as long as I can remember, I've suffered intermittently with nightmares, waking up occasionally to huge adrenalin rushes. Sometimes I lie in bed and try to picture what is going on at a molecular level in my body. Every year in school, I fill in the details in this picture a little more. This year I've flushed it out quite a bit.

Let's start with epinephrine or norepinephrine binding to the β1-adrenergic receptor in the heart. The β-agonist-receptor complex binds to a stimulatory guanine nucleotide binding protein (Gs), which is then activated. The activated Gs stimulates adenylyl cyclase to produce more cAMP, which leads to the activation of cAMP-dependent protein kinase (PK-A).
Activated protein kinase A phosphorylates several sites within the cardiac cell, notably:

• the L-type calcium channel
• phospholamban, a regulator of sarcoplasmic reticulum calcium pump activity
• troponin I
• the cardiac ryanodine receptor (RYR2)

Let's tackle the effects of these phosphorylation events one by one.

Phosphorylation of the L-type calcium channel makes it more likely that the channel will open when an action potential depolarizes the membrane potential. Calcium channels are different from sodium channels because in addition to voltage and time dependent gates they have a calcium dependent gate/regulatory component. My professor, Dr. Gilmour, writes, "In the resting state, a certain fraction of the phosphorylation-dependent gates are phosphorylated and are, therefore, open. However, no current can flow through the channel because the voltage-dependent activation gate is closed. As the cell is depolarized past the threshold for opening of the activation gate, the channel opens and calcium enters down its concentration gradient." He adds, "The primary physiological mechanism for increasing ICa is augmentation of calcium channel phosphorylation by activation of β-adrenergic receptors."
What does this mean? More open calcium channels means more calcium ions entering the cell and this leads to more calcium released from the sarcoplasmic reticulum via calcium-induced calcium release and this culminates in an increased strength of conraction. (From Dr. Fewtrell, "The calcium ions binds to troponin C which allows myosin to bind to actin. Calcium influx into mitochondria also stimulates mitochondrial metabolism to provide the ATP necessary to sustain contraction.") In short, by phosphorylating L-type calcium channels you get increased contractility (i.e. heart pounding)

What happens when you phosphorylate phospholamban? First off, phospholamban is an inhibitor of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA) pump. The function of this pump is to pump calcium back into the sarcoplasmic reticulum (SR). When phospholamban is phosphorylated it can no longer inhibit the SERCA pump, which means that calcium is pumped back into the SR more rapidly. This leads to faster relaxation in the cardiac myocyte. As a result of being able to relax more quickly, the cardiac myocyte can also contract again more quickly, hence the ability to raise the heart rate significantly (it might seem counter-intuitive that relaxing more quickly would lead to a higher heart rate but in order to contract, a cell must first relax so that the ion channels are not in the refractory state where they can't be stimulated, i.e. closed).

Phosphorylating troponin I decreases its affinity for calcium ions, which also promotes relaxation, in this case by removing it from the myofilaments. Faster relaxation means that the cardiac cell can contract again more quickly, enabling a higher heart rate.

Phophorylation of the ryanodine receptor (RYR2 in cardiac myocytes) increases the permeability of the ryanodine receptor to calcium and leads to more calcium being released, which leads to more calcium binding to troponin C and more actin-myosin interactions and ultimately an increased strength of contraction.
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This still doesn't answer the question of how adrenaline raises your heart rate, it just explains how it is possible to achieve a higher heart rate, not where the actual signal comes from. I know that epinephrine and norepinephrine bind to β1-receptors in the sinoatrial (SA) node. So I consulted the internet and found that they decreases the conductance for potassium and increases the conductance for calcium and sodium, which means the pacemaker current If (the funny current) is enhanced. As a result the pacemaker potential reaches threshold more quickly and there is a faster firing rate from the SA node that sets the heart rate (i.e. heart racing). Don't hold me to this because it is not from my notes.

So there, that's a fair amount to think about next time you are lying in bed at night awake. And I didn't even touch on the α1-agonist effects of epinephrine and norepinephrine that are occurring simultaneously!