voltage gated K+ channel? inhibiting channels? You are studying a new virus whos

Question

voltage gated K+ channel? inhibiting channels?

You are studying a new virus whose effects include loss of motor control in all limbs due to an imbalance of intracellular potassium ions. You discover that this is due to viral induced depolarization of nerve membranes, resulting in constitutive activation of the voltage-gated K+ channel. You begin to design drugs that will stop the passage of K+ ions through this channel. Based on your mechanistic knowledge of the physical characteristics and mode of regulation of the voltage-gated K+ channel, describe two strategies whereby new drugs could inhibit K+ ion flow through this channel.

Explanation / Answer

The chemicals that can modulate voltage-gated potassium channels broadly fall into 3 categories like metal ions, venom derived peptides (3 to 6 k Da) and organic small molecules (MW 200 to 500 Da).

The ways by which these chemicals affect the voltage-gated potassium ion channel functioning is by inhibiting the ion conducting pore from outside or inside or by changing the channel gate through binding to the voltage-sensor domain or auxiliary subunits.

Voltage-gated potassium channels are targeted using antibodies, which can block the channel function, result in channel internalization or exhaust the channel expressing cells by cell-mediated toxicity or by complement. Engineered antibodies and toxins can act as carriers of active compounds to channel expressing cells or can be conjugated to cytotoxic drugs, other molecules or isotopes. In some studies, monoclonal antibodies are used for channel inhibition and in many cases, polyclonal antibodies were raised against the antigenic region of the extracellular parts of the pore loop.

The action of peptide toxins on the voltage gated potassium channels is by binding to the outer vestibule or the voltage sensor of potassium channels. A few small molecules similar to hydrophobic cations like tetra butyl ammonium, d-tubocurarine and verapamil inhibit the voltage gated potassium channels by blocking the inner pore with the help of ammonium group insertion into the ion permeating hole. The inside pores of the potassium channels can also be blocked by nucleophilic molecules like correolide which hooks at the hydrophobic surface of the S6 helix with its lipophilic part and attaches to the permeating potassium ion with the help of its polar acetyl groups.

The typical inhibitors of this channel enter it from the intracellular region and stays in the pocket towards inside to interact with the two aromatic residues.

There are several varieties of drugs that the inner pocket can accommodate featuring the absence of cluster of prolines and induce the potassium channels in contrast to the other family of drugs. Therefore, there is a wide range of opportunity for the drugs to be designed in various shapes and sizes for the voltage gated potassium channels.

Potassium channels are diverse class of ion channels and the targets created for them will provide an incredible potential in the treatment of human diseases involving aberrant expression and function of specific potassium channels. The drugs that work on KATP, KCNQ and HERG (Kv11.1) channels were studied and used respectively in clinics for the treatment of epilepsy, diabetes or hypertension and cardiac arrhythmia.

The cancer therapeutic efficacy study on the potassium channels is done focusing on the EAG channel family that includes EAG1, EAG2 and HERG. Over-expression of EAG1 provides potential for the growth of tumor. Small molecule blockers of EAG1 such as astemizole have provided efficacy in decreasing the EAG1 expressing cancer cell growth in in-vivo and in-vitro studies.

Rational design of the targets for potassium channels for cancer treatment can be done by studying clearly the mechanical functioning of the channels. One of the methods is that cancer cells express N-terminal truncated form of HERG channel that can be used for creating an antagonist of isoform-specific type. One of the current studies has identified a lipid raft localized SK3 potassium-Orai1 calcium channel complex, which can be used for controlling breast cancer. Destroying the lipid rafts with alkyl lipid ohmline results in decreased bone metastasis. This compound is shown to be effective in targeting the potassium channel protein complexes indirectly influencing the major processes of cancer progression. A potential adjuvant therapy can also be made by exploiting the potassium channel antagonism.

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