In vitro pharmacology of Kv channels: new modes of diversity and modulation
27 April 2017
UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Dirk Snyders, Alain Labro, Jan Tytgat
PhD defence Jeroen Stas - Department of Biomedical Sciences
Voltage-gated potassium (Kv) channels are key determinants of cellular excitability and their role in many (patho)physiological conditions has been well established. They are valuable drug targets for many hyperexcitability-related disorders, metabolic diseases and they can be targeted to provide neuroprotection in neurodegenerative diseases. However, the high diversity of Kv channel members and their complex regulation by auxiliary subunits and posttranslational modifications has challenged the field of Kv channel pharmacology for decades.
In recent years, many new lead compounds were identified from different venomous animals such as sea anemones and scorpions. Together with the revelation of many regulatory processes of Kv channels, this has fueled the field of Kv pharmacology for the development of more selective Kv channel targeting compounds. The goal of this doctoral thesis was to further contribute to this ongoing revolution in the field by investigating three aspects of Kv channel pharmacology:
(i) Despite their proven value to drug discovery, the venom from animals such as sea anemones remains a mainly untapped source for the identification of novel lead compounds. We investigated whether a novel identified sea anemone toxin (BcgTx) had the potential to modulate Kv channels in an in vitro setting. Using the patch clamp technique for our investigation, we determined that BcgTx is the first reported peptide toxin to target the Kv1.4 and Kv1.5 channels and its mechanism of action is novel to the Kv1 subfamily.
(ii) Members of the silent Kv (a.k.a KvS) subfamilies have been suggested to be promising targets for drug therapy because of their obligatory heterotetramerization with Kv2 subunits and their unique expression pattern in organisms. However, little is known about their pharmacological profile and the underlying mechanism in which they could alter the Kv2 pharmacological response. In this doctoral thesis, we demonstrated that KvS subunits, especially the Kv6.4 subunit, drastically alter the Kv2 pharmacology and provide unique pharmacological properties to Kv2/KvS heterotetrameric channels.
(iii) Several Kv channel targeting lead compounds have reached the clinical stage over the course of the last decade. However, reports of toxicity problems upon long-term exposure to some of these compounds has raised the question whether other, off-target, Kv channels might be involved. We investigated the Kv channel selectivity profile of some of these compounds and discovered an unreported capability to inhibit other Kv channels in an irreversible manner.