mirams/ephys-reading-help

To make reading easier for modellers. It's not an encyclopedia.

Reading help | Review list | Ionic concentrations

Terminology for reading cardiac cell ephys lit

Goal is to make reading easy / possible. It's not an encyclopedia.

Currents

Below is a deliberately incomplete and oversimplified list of ionic currents in cardiac excitable cells, along with protein names, gene names (primarily the alpha subunits), some famous blockers, and unfortunate names still used in the literature.

Current	Protein(s)	Famous genes	Subunit genes	Famous blockers	Nicknames
INa, INaL	Nav1.5	SCN5A	SCN1B, SCN2B, SCN3B, SCN4B	Tetrodotoxin (TTX), STX
ICaL	Cav1.2 (V)	CACNA1C	CACNB2, CACNA2D1	Nifedipine
	Cav1.3 (A)	CACNA1D	CACNB2, CACNA2D1	Nifedipine
ICaT	Cav3.2	CACNA1H
IKr	Kv11.1	KCNH2	KCNE2	Dofetilide	HERG
IK1	Kir2.1	KCNJ2
IKs	Kv7.1	KCNQ1, KCNE1			LQT1
Ito	Kv4.3	KCND3
If		HCN4
IKur	Kv1.5	KCNA5

Current	Enzyme	Famous genes	Subunit genes	Famous blockers
INaK (Ip)	Na/K-ATPAse			Ouabain
INaCa (NCX)
	RyR
	SERCA

Notes / Questions / TODO

• IClCa=Ito2, Ito=Ito1, IKur=IKp?
• Nav2.1 (SCN7A) also prevalent in heart?
• Gaborit Kv4.3 expr is surprising
• Other Kirs expressed in several places
• Kv1.7 (KCNA7) said to be similar to similar to Kv1.5 and important in atria

Why all these names?

• The current is usually discovered long before the carrier (proteins/enzymes encoded by several genes).
• The gene products assemble in macromolecular complexes, which interact with other stuff in the cells. The current in the "Current" column is the current through these assemblies, present only in the native cell.
• To measure these, you need to get rid of other currents measured simultaneously, so you apply a blocker which you hope is specific, but which you suspect might not be, and so it is often "more correct" to say "we measured the dofetilide-sensitive current" rather than "we measured IKr". It also happens that currents are discovered through blockers, so the blocker is known before the current is named.
• In expression systems (CHO, HEK, Oocytes) you often express only the alpha subunit, so the channels lack all sorts of things they have in the real cells, and it can be more accurate to say "we measured a KCNH2 current" than "we measured IKr".
• Finally, a lot of genes had strange names until they became standardised. For example, "hERG" for "human Ether-a-go-go-Related Gene" because it is similar to a gene that made fruit fly legs twitch in early experiments. Some diseases have been classified by the genes suspected to underlie them, e.g. long QT syndrome got split into types according to various channel genes, where "LQT1" is the variant caused by IKs mutations. This then rubbed off onto the gene KCNQ1, so that some publications call it LQT1!

Awesome reviews, per current

Awesome references for currents given below. Bonus points if you can limit it to 1 ref per current.

Current	Awesome ref
IKr	Vandenberg et al. (2012)
ICaL	Striessnig et al. 2014
	Zamponi et al. 2015
	Hess 1988
INa	Grant 2001
	Chadda et al. 2017
INaK	Glitsch 2001

More comprehensive current/channel/gene lists

• Gaborit, Le Bouter et al., Nattel (2007) Regional and tissue specific transcript signatures of ion channel genes in the non‐diseased human heart
• EPFL Channelpedia
• IUPHAR/BPS List of channels

Nervous system

Autonomic nervous system (ANS) controls lots of organs (subconciously) including effects on the heart rate.

It's divided into sympathetic ("fight-or-flight"), parasympathetic ("rest-and-digest"), and enteric (your "gut brain" in popular science).

Part of ANS	Famous effect	Famous neurotransmitter	Famous receptors	Famous nerves
Sympathetic	Faster	Epinephrine (Adrenaline)	(Beta-) Adrenergic
		Experiments use Isoproterenol (iso)
		Norepinephrine (Noradrenaline)
		Catecholamines
Parasympathetic	Slower	Acetylcholine (ACh)	Muscarinic, Nicotinic	Vagus ("Vagal")

Annoying terminology

Depolarisation

• When a membrane potential goes "up" from its resting potential value towards zero it "depolarises".
• When a membrane potential goes "back down" from higher voltages towards its resting potential it "repolarises"
• When a membrane potential goes "down" from its resting potential value further from zero it "hyperpolarises".
• These terms are really useful when describing the resting potential, because a "higher resting potential" is ambiguous (bigger difference or higher value of V?).
• However, also used for membrane potential, where it gets annoying, with authors even calling a change from 10mV to 30mV a "depolarisation".
• (In 1902 the resting potential and action potential had been observed, but the membrane is much too small for light microscopy. Julius Bernstein proposed the existence of a membrane to explain the resting & action potential, and further hypothesised "membrane breakdown" as the explanation for depolarisation accompanied by changes to ion permeabilities. Kenneth Cole & collaborators performed early voltage-clamp experiments in the 30s and 40s and found that the membrane potential did not go to zero, but went to positive values, which they called "overshoot". This disproved the "membrane breakdown" idea, and maybe should have inspired some better terminology).

Activation, deactivation, inactivation, recovery

• In a simple 2 gate HH model, the INa current activates when the cell is stimulated (opening it up), and then inactivates at higher voltages (closing it down)
• A consistent way of using the words is to view activation & deactivation as the same reaction, but in opposite direction; and to view inactivation & recovery from inactivation as the two directions of a separate reaction. So for INa we start deactivated & recovered (closed), then become activated & recovered (open), then activated & inactivated (closed), then deactivated & inactivated (closed), then finally deactivated & recovered again.
• These terms are not used consistently in the literature. Deactivation particularly is often treated as a separate process (not the reverse of activation).
• In HH's model, only INa inactivated/recovered. Later other currents were found to do it too.
• INa activates/deactives rapidly, inactivates/recovers slowly. A ball-and-chain metaphor is usually invoked, saying the C-terminus of the alpha subunit blocks the pore after opening.
• For currents like IKr this is radically different, with inactivation/recovery being much faster, and no consensus view on whether it depends on activation/deactivation.

Inotropic / Lusitropic

• "Positively inotropic" = increases strength of contraction / contractility
• "Negatively inotropic" = decreases strength of contraction / contractility
• "Positively lusitropic" = increases rate of relaxation