Author Topic: A review of potassium channels in mood (ie. Bipolar Disorder treatment)  (Read 137 times)

Offline Chip (OP)

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source: https://www.frontiersin.org/articles/10.3389/fgene.2013.00105/full

The Review

Although bipolar disorder (BP) is one of the most heritable psychiatric conditions, susceptibility genes for the disorder have yet to be conclusively identified.

It is likely that variants in multiple genes across multiple pathways contribute to the genotype–phenotype relationship in the affected population.

Recent evidence from genome-wide association studies implicates an entire class of genes related to the structure and regulation of ion channels, suggesting that the etiology of BP may arise from channelopathies.

The term “channelopathy” is a relative newcomer to the medical lexicon, referring to disorders that result from defective ion channel functioning.

In this review, we examine the evidence for this hypothesis, with a focus on the potential role of voltage-gated potassium channels.

We consider evidence from genetic and expression studies, and discuss the potential underlying biology.

We consider animal models and treatment implications of the involvement of potassium ion channelopathy in BP.

Finally, we explore intriguing parallels between BP and epilepsy, the signature channelopathy of the central nervous system.

... another excerpt

Genetic Epidemiology

Bipolar disorder (BP) is a disabling psychiatric condition with a considerable public health impact, affecting 1–2% of the general population (Weissman et al., 1996).

Family, twin, and adoption studies show that genetic factors play a leading role in is etiology.

Family studies suggest that compared to the general population the risk of BP is 5–10 times greater in siblings of a proband with the disorder (Craddock and Jones, 1999) and twin studies provide estimates of heritability for BP that range from 80 to 90%, ranking it among the most heritable of psychiatric disorders (Barnett and Smoller, 2009).

However, conclusive findings from molecular studies to identify relevant genetic factors have proven elusive, and the genetic architecture remains unresolved.

Although results from sequencing analyses may reveal rare variants with large effects on the level of the individual, single variants are not likely to influence BP risk at the population level (Craddock and Sklar, 2009).

Rather, multiple genetic phenomena likely contribute to BP risk, including the additive and interactive effects of many variants, each contributing a small effect, as well as heterogeneity across populations.

This has lead to an interest in identifying the molecular pathways that are disrupted by these risk variants, any number of which may underlie an individual’s susceptibility to BP (Askland et al., 2009).

Ion Channels as Therapeutic Targets

Ion channels provide an attractive target for pharmacological intervention, given their diverse and ubiquitous roles in a broad range of physiological processes. Among all drugs with known targets, approximately 13.4% have their primary therapeutic action at ion channels. This ranks ion channels second as a target class, behind G protein-coupled receptors (GPCRs; Overington et al., 2006).

Accumulating evidence suggests that existing treatments for BP may potentially exert their therapeutic action via ion channel regulation (Gould et al., 2004). Lithium, a simple monovalent cation, is a first-line treatment for BP (Quiroz et al., 2004). Although its mechanisms of action are not entirely clear (O’Brien and Klein, 2009), there is some evidence that it affects ion channel functioning.

A recent investigation of in vitro lithium treatment in mouse brain tissue determined that, at therapeutic concentrations, lithium entered the cell through sodium channels and suppressed the outward membrane current, which directly affected membrane excitability (Butler-Munro et al., 2010). The authors concluded that ion channels that regulate neuronal excitability may be a common target among BP treatments.

Lithium is also a direct and potent inhibitor of glycogen synthase kinase 3β (GSK3β; Klein and Melton, 1996; Quiroz et al., 2004). GSK3β has many functions, one of which is to phosphorylate the voltage-gated potassium channel KCNQ2. It has been shown in vitro that phosphorylation of KCNQ2 decreases the activity of the channel and subsequently reduces the M-channel current (Borsotto et al., 2007).

It is intriguing to speculate that lithium may have therapeutic effect by blocking this downstream phosphorylation of KCNQ2. Antiepileptic drugs (AEDs) such as valproate, lamotrigine, and carbamazepine have a long history of successfully treating BP, and may similarly affect the regulation of neurotransmission and action potential firing via mediation of ion channel functioning.

The AEDs that are effective against BP likely have multiple molecular targets with variable contributions to the drugs’ efficacy (Perucca, 2005). However, it is notable that they are all known to diminish the flow and accumulation of sodium ions in the cell (El-Mallakh and Huff, 2001).

Voltage-gated potassium channels, specifically the Kv7 channels, are particularly attractive targets for novel therapeutics for BP.

In addition to their functionally relevant roles within neurons, they offer the ability for selective intervention (Brown and Passmore, 2009). For example, ezogabine (EZG) is a neuronal potassium channel enhancer that was recently approved by the FDA (Food and Drug Administration) to treat partial epilepsy (Little, 2009).

It has been shown (Wickenden et al., 2000) that EZG activates the KCNQ2/KCNQ3 hetero-tetramer ion channel complex, which in turn promotes the M-current and thereby stabilizes action potential firing. This action likely accounts for the drug’s anticonvulsant properties (Borsotto et al., 2007).

Several groups have studied the potential mood-stabilizing effects of EZG and other Kv7 channel enhancers in a series of animal studies. One study (Redrobe and Nielsen, 2009) used a mouse model of mania and determined that EZG (a non-selective opener) and ICA-27243 (a selective Kv7.2/3 opener), but not BMS-204352 (a selective Kv7.4–Kv7.5 and Kv7.7/3 heteromer opener) were able to reduce motility in the hyperactive mice, a paradigm for antimanic properties in drugs. In another study employing the D-amphetamine and chlordiazepoxide (AMPH + CDP) mouse model (Kristensen et al., 2012), EZG reduced cerebral glucose metabolic activity while increasing phosphor-serine-9 levels of GSK3β with a brain regional signature that mirrored lithium and valproate.

Ezogabine has also been evaluated for the acute treatment for mania in a small (N = 10) open label pilot study of treatment resistant in patients with BP type I (Amann et al., 2006). Despite the limited sample, the brevity of the study design, and the severity of illness, improvement in mania scores was observed in four patients. The treatment was well tolerated with no depressogenic effects, indicating that further study may be warranted.
« Last Edit: June 01, 2019, 03:13:38 PM by Chip »
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