Group Presentation on Stahl Readings part I

Voltage-sensitive Ion Channels As Targets of Drug Action

What are Ion Channels?

What? Pore-forming protein complexes that facilitate the flow of ions across the hydrophobic core of cell membranes

WHERE? Plasma membrane and membranes of intracellular organelles of all cells

WHY? Involved in muscle contraction/relaxation, neuronal signal transmission, neurotransmitter release, cognition, hormone secretion, sensory transduction, electrolyte balance, and blood pressure

Basics of How they work

Gates are opened or closed depending on ionic charge or voltage potential

The opening of the gates change the polarity of the cell membrane

A  series of these changes move along the neuron

There are 4 major ions involved. Sodium, Calcium, Potassium & Chloride. Most Na+, K+, Ca2+ and some Cl- channels are gated by voltage, whereas others are relatively voltage-insensitive and are gated by second messengers and other intracellular and/or extracellular mediators (Pharmacology Education Project, 2019)

Ion channels are classified by gating the stimulus that opens and closes the channel, be it chemical or mechanical stimuli, and are regulated by the ionic charge or voltage potential across the membrane in which they reside (Pharmacology Education Project, 2019)

 

These channels exist in 3 states: open, closed/resting, and inactive state . Certain ion channels undergo conformational change on binding with molecules and can thus switch between the three states within milliseconds (Jacob, 2017). Critical aspects of nerve conduction, action potentials, and neurotransmitter release are all mediated by ion channels that are "voltage sensitive" or "voltage gated" ion channels (Stahl, 2013)

Our next slide will show a video of these gates in action.

An electrical impulse in a neuron, also known as the action potential, is triggered by summation of the various neurochemical and electrical events of neurotransmission . Voltage sensitive ion channels are opened and closed by the voltage charge across the membrane (Stahl, 2013)

Voltage Gated Ion Channels are rapid, exhibit highly selective permeability, and are responsive to changes in the local electrical membrane potential which are critical for the function of excitable cells, such as neurons and muscle cell and are subject to conformational change based on changing membrane potential (Jacob 2017).

Electrically, the first phase of the action potential is sodium rushing "downhill" into the sodium-deficient, negatively charged internal milieu of the neuron made possible when voltage-gated sodium channels open the gates and let the sodium in (Stahl, 2013).

A few milliseconds later, the calcium channels get the same idea, with their voltage-gated ion channels opened by the change in voltage potential caused by the sodium rushing in (Stahl, 2013).

Voltage-gated ion channels hare not as simple as just a pore in the cell membrane. These channels are long strings of amino acid that contain 4  subunits. Each subunit has six transmembrane segment. Transmembrane #4 acts like a volt meter (it’s the one in the picture with the lightning bolt) when it detects a change it alerts the rest of the protein.  The final result is that the ion channel either opens or closes. Each subunit of a voltage sensitive ion channel has an extracellular amino acid loop between transmembrane segments 5 and 6. This serves as an “ionic filter” (think of a colander which allows only certain ions to filter through) (Stahls, 2013)

· Sodium is kept out of the neuron when the channel is closed/inactivated and the direction of sodium flow is into the neuron when the channel is open/activated

· Voltage-sensitive sodium channels may have regulatory proteins, known as beta units, located in the transmembrane area and flanking the alpha pore-forming unit.

· Beta subunits may indirectly influence the opening and closing of the channel.

· Various sodium channels may be the sites of action of several anticonvulsants, some of which have mood stabilizing and pain reducing properties.

Voltage Sensitive calcium Channels

Amino acids connecting the second and third subunits of the channel work as a “snare” to hook up with the synaptic vesicles and regulate the release of neurotransmitter into the synapse during synaptic neurotransmission (Stahl, 2013).

• The direction of ion flow is from outside the cell to inside the cell when the channel opens to allow ion flow to occur (Stahl, 2013).

• Downstream of the depolarization induced by calcium activates calcium-dependent non-specific cationic channels which maintains the neuron in a depolarized state (Altunrende et al., 2018).

· Approximately 10% of psychotropic medications have voltage gated ion channels as their mode of action

· Various voltage sensitive sodium channels may be the sites of action of several anticonvulsants, some of which have mood stabilizing and pain reducing properties. These would gabapentin, pregabalin, lamotrigine, carbamazepine, oxcarbazepine, and zonisamide.

· The specific subtypes of  voltage sensitive calcium channels of most interest to psychopharmacology are those that are presynaptic, that regulate neurotransmitter release, and that are targeted by certain psychotropic drugs 

Together, ligand-gated and voltage-sensitive ion channels work cooperatively during neurotransmission communicating with between a mix of electrical and chemical messages made possible by ion channels