Heterotetrameric channels of Kv2 and 'silent' Kv subunits: stoichiometry and physiological function
27 September 2016
UAntwerpen, Campus Drie Eiken, Auditorium R3, Gebouw R - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Dirk Snyders, Elke Bocksteins
PhD defence Glenn Regnier - Faculty of Pharmaceutical, Biomedical and Veterinary Sciences
Voltage-gated potassium (Kv) channels are transmembrane tetramers of individual α-subunits. Some 40 different α-subunits have been identified which are subdivided into twelve subfamilies (Kv1-Kv12) based on sequence homology. Members of the Kv5, Kv6, Kv8, and Kv9 subfamilies are designated as ‘silent’ Kv (KvS) subunits since they are unable to form functional homotetramers; instead they form heterotetramers with members of the Kv2 subfamily.
Due to their involvement in a variety of physiological processes, Kv channels are imporant pharmacological targets. However, the ubiquitous expression of Kv2.1 may be a limiting factor for the development of therapeutics targeting Kv2.1 channels. KvS subunits have a more confined expression pattern suggesting that several Kv2/KvS heterotetramers have distinct tissue-specific functions. Therefore, Kv2/KvS heterotetramers may be more desirable pharmacological targets for novel treatments. The goal of this doctoral thesis was to contribute to the promising therapeutic potential of Kv2/KvS heterotetramers by elucidating three different aspects of KvS function:
(i) The pharmacological properties of heterotetrameric Kv channels are often affected by the stoichiometric and positional arrangements of the involved subunits. Therefore, in order to design drugs that target Kv2/KvS channels, it is important to know the possible stoichiometric configurations of these channels. Using Kv2.1/Kv6.4 as a model, it was demonstrated that stoichiometry can be either 3:1 or 2:2 with the restriction that Kv2.1 and Kv6.4 have to alternate in the channel complex.
(ii) It is thought that hyperexcitability of dorsal root ganglion (DRG) neurons is a major issue in pain transmission. Kv channels are therefore regarded as key targets in the development of future pain treatments. Consequently, it is important to know how Kv channel expression changes during postnatal development in these neurons. It was demonstrated that the expression of Kv2.2 decreases with age, while the expression of Kv2.1 remains stable. Furthermore, there were some age-dependent fluctuations in the expression of Kv6.3, Kv8.1, Kv9.1, and Kv9.3.
(iii) Several KvS subunits are expressed in mammalian testis tissue, but information about their contribution to testicular function is lacking. We demonstrated that the targeted deletion of Kv6.4 in a mouse model causes male infertility which was due to disturbed spermiogenesis.