Page 7 - CBAC Newsletter 2016
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were found to carry the M-current (2). KCNQ2/3 familial neonatal convulsions in an infant were found
heteromeric channels were mainly named the classical to be associated with mutations in KCNQ2 and KCNQ3
M-current (7,12,74). KCNQ2 and 3 are chiefly expressed channels (4,92). Reduction of M-current is also
in the nervous system, where they colocalize in some associated with tinnitus, autism, and bipolar disorders
neuronal populations (75,76). This finding may suggest (4,92-96), and with types of progressive hearing loss
that these channels are assembled in a subset of linked to mutations in KCNQ4 (6).
neurons and are expressed as heteromeric channels The M-current was first identified in bullfrog sympathetic
(75-77). However, they are not always colocalized in ganglia (73). The equivalent mammalian channels were
brain tissues (75). There is also evidence that KCNQ2 identified in the superior cervical ganglion (SCG) of rats
homomeric channels are expressed in vivo (78-80). (97). Studying M-current was difficult until selective
Additionally, KCNQ5 may also be expressed heteromeric agents acting on these channels were discovered such
channels with KCNQ3 (7). as linopirdine and XE991, allowing researchers to screen
It was found that all KCNQ channels need PIP2 known K+ channel genes (10). Such selective ligands
(phosphatidylinositol 4,5-bisphosphate), a phospholipid help to screen various channels pharmacologically, to
in the inner leaflet of the plasma membrane, for compare their distinctive biophysical properties, and to
activation (81). PIP2 is required for the movements study the expression of many subunits of both
in the voltage sensor domain to trigger the pore gate homomeric and heteromeric channels. Thereafter,
domain to open (82,83). Thus, KCNQ channels are both KCNQ2/3 heteromeric channels were explored as
voltage-gating and ligand-regulating potassium M-current channels in the SCG of rats (12,75). This
channels. M1 muscarinic activation activates history highlights the importance of pharmacological
phospholipase C by G-protein (Gq), which hydrolyzes agents as tools in the study of KCNQ channels.
PIP2, thereby inhibiting KCNQ channels (84). M-current KCNQ subunits are diverse in their assembly, forming
channels can control the rate of neuron firing because both homomeric and heteromeric channels. The
of their special biophysical properties and subcellular assembled channels have various phenotypes, differing
localization (76,85), and they can further potentiate in their expression level, cellular targeting, biophysical
membrane excitability, due to downregulation as a result characteristics, and pharmacological profiling. The
of G protein-coupled cell signaling. This is an important composition of expressed channels in vivo is difficult to
balancing regulatory pathway of M-current physiology know for certain, however, studying their characteristics
(2,3,86). and comparing them with channels that express in vtiro
Inhibition of M-current in a mouse model leads to offer insights in to the subunits’ composition in various
disorder in hippocampus-dependent spatial memory human tissues (13). Information about KCNQ subunits
(15). In rodent models, acute stress can cause impaired and tissue-specific localization, combined with drug
retrieval of the hippocampus-dependent spatial memory discovery approaches using potent selective ligands,
(87,88). Acute stress has been shown to raise the would improve our knowledge and advance treatment
output of 5-hydoxytryptamine (5-HT) in the hippocampus therapeutics. In this article, we review the compounds
(89,90). 5-HT was reported as an inhibitor of M-current that either activate or inhibit channels, assessing their
channels in mammalian neurons (91). Therefore, specificity to various KCNQ channels, their mechanism
M-current channels might be involved with the acute of action, and their use in research and therapy.
stress that causes disruption of spatial memory retrieval
and synaptic plasticity. In addition, a study has reported KCNQ Channel Activators
a decrease in KCNQ with aging in brain tissues of 1. Retigabine ‘RTG’ (D23129)
drosophila (25), and KCNQ3 channels were reduced in In 2011, the drug retigabine (RTG) finished clinical trials
the mice hippocampus after object recognition training as the first approved KCNQ channel opener for human
(26). use. RTG has a novel binding site and mechanism of
KCNQ2/3 channels maintain neuronal excitability at action for activating the KCNQ 2-5 channels, but not the
a normal level. Any decreases in M-current activity related cardiac KCNQ1 subunit (Fig.2) (98-101). RTG
because of genetic or other factors are directly linked has an effect on a range of seizure disorders, and it has
to neuronal hyperexcitability-associated disorders, such been approved by the FDA as an antiepileptic drug for
as epilepsy. This disease is characterized by recurrent the treatment of partial/focal seizures (98,102).
seizures due to synchronized electrical hyperexcitability
in the central nervous system. For instance, benign
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