An increasing number of recent reports on potassium SK/K_Ca2 and IK/K_Ca3.1 channels elucidate their multifaceted functions in cell motility, neuronal excitability, neuroprotection, and neuroinflammation (Stocker, 2004; Schlichter et al., 2010; Allen et al., 2011; Dolga et al., 2011). In fact, based on the plethora of functions exerted by SK/K_Ca2 channels, modulators of these potassium channels have been proposed for therapeutic applications in a wide variety of pathological conditions, including brain tumors, cerebral ischemia, schizophrenia, Parkinson’s and Alzheimer’s diseases, and other neurological diseases where neuroinflammatory mechanisms are considered as major hallmarks (see Table 1; Rupalla et al., 1998; Wyss-Coray and Mucke, 2000; Liégeois et al., 2003; Yan et al., 2003; Stocker, 2004; Judge et al., 2007; Hirsch and Hunot, 2009; Schlichter et al., 2010; Allen et al., 2011; Dolga et al., 2011, 2012; Varas-Lorenzo et al., 2011; Herrik et al., 2012; Kuiper et al., 2012). For example, riluzole, a drug used in patients with amyotrophic lateral sclerosis (ALS) and hereditary cerebellar ataxia, is a potent activator of SK/K_Ca2 channels (Grunnet et al., 2001; Cao et al., 2002) that reduces neuroinflammation and neuronal excitability (Judge et al., 2007; Waubant, 2007; Ristori et al., 2010; Liu et al., 2012; see Table 1). Recently, derivatives of 2-(phenylamino)benzimidazole and 2-amino benzimidazole were patented as novel SK/K_Ca2 channel modulators for therapeutic applications in Alzheimer’s disease, anxiety, and ataxia (Sørensen et al., 2006a,b).

Patch-clamp studies of microglial cells showed that these cells express a wide variety of potassium channels. These include inward rectifier K⁺ (Kir) channels (described in rat, murine, bovine, and human microglia), delayed outwardly rectifying K⁺ (Kdr) channels (described in rat, mouse, and human microglia), human ether-a-go-go-related gene (HERG) K⁺ channels (described in rat microglia), G protein-activated K⁺ channels, ATP-sensitive potassium (K_ATP) channels, and voltage independent calcium-activated potassium (SK/K_Ca2) channels (described in murine, bovine, and human microglia; Eder et al., 1997; Eder, 1998). Several studies demonstrated that microglial potassium channel activity promotes neuronal survival and reduces microglial activation and related neuroinflammation (Polazzi and Monti, 2010; Kettenmann et al., 2011). For example, K_ATP channel activation using diazoxide exerted anti-inflammatory effects in LPS and interferon gamma (IFNγ)-activated mouse primary microglial cells in vitro (Virgili et al., 2011). Diazoxide, a classical K_ATP channel activator, prevented rotenone-induced rat microglial activation (Zhou et al., 2008), inhibited NO release, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) production, and inducible nitric oxide synthase (iNOS) expression in a mouse model for multiple sclerosis in an induced experimental autoimmune encephalomyelitis (Virgili et al., 2011).

All subtypes of small-conductance calcium-activated potassium KCNN1-3/SK1-3/K_Ca2.1–3 channels have been identified in neuronal cells of different species, including mouse, rat, and human neurons (Köhler et al., 1996; Sailer et al., 2004; Dolga et al., 2011). In neuronal cells, SK/K_Ca2 channels are activated by submicromolar calcium concentrations (K_D ∼ 0.5 μM) due to the calcium sensing binding site, a calmodulin (CaM)-binding domain located at the C-terminus of β-subunits (Adelman et al., 2012).

Functional SK/K_Ca2 channels consist of four subunits, each with six transmembrane segments and cytosolic N and C termini (Stocker, 2004). Upon increasing intracellular calcium concentrations, CaM interaction to CaM-binding domain (CaMBD) alters the geometry of the C-lobe E-F hands from one subunit of SK/K_Ca2 channels by binding to a neighboring subunit and forming a dimer that promotes a conformational rotation of CaMBD, allowing potassium flow through the channel pore (Xia et al., 1998; Adelman et al., 2012). It is well established that SK/K_Ca2 channels mediate afterhyperpolarization (AHP) in response to an action potential in excitable cells. Opening of SK/K_Ca2 channels promotes a negative resting membrane potential or even hyperpolarizing, preventing the onset of a second action potential. Thus, SK/K_Ca2 channels act as fine tuning regulators of action potential frequencies, neuronal excitability, and [Ca²⁺]_i (Stocker, 2004).

SK/K_Ca2 channels are responsible for the medium AHP (mAHP), which decays in 200 ms (Bond et al., 2004), while BK channels are responsible for the fast AHP component, which decays in 50 ms (Faber and Sah, 2003). SK/K_Ca2 channels possess a small unitary conductance (∼10 pS in symmetrical potassium; Köhler et al., 1996) and exhibit an inward rectification. The general knowledge of the inward rectification of SK/K_Ca2 channels is attributed to the block of outward current by divalent ions, such as Ca²⁺ and Mg²⁺ (Lu, 2004), as it is the case for inward rectifier K⁺ channels (Kir, IRK). However, it was recently shown by inside-out patch-clamp recordings of rat SK2/K_Ca2.2 channel activity that three negatively charged residues in the sixth transmembrane domain could also be responsible for the SK/K_Ca2 channel inward rectification (Li and Aldrich, 2011). Importantly, these negatively charged residues affect the Ca²⁺ affinity for SK/K_Ca2 channel gating, and the open probability (P_o) of the channel in the absence of Ca²⁺ and this intrinsic inward rectification is largely attributed to a voltage-dependent reduction in outward single-channel conductance (Li and Aldrich, 2011). However, in specific neurons, such as in the rat nucleus basalis, in the rat ventral midbrain, or in preoptic rat hypothalamus, SK/K_Ca2 channels are responsible for slow “spontaneous miniature” outward currents (Arima et al., 2001; Cui et al., 2004; Klement et al., 2010). The precise function of these outward currents has not yet been elucidated, however, it has been suggested that they may also contribute to spontaneous firing, hyperpolarization, and regulation of burst firing (Adelman et al., 2012).

Several acute and chronic pathologies, including Alzheimer and Parkinson’s disease, multiple sclerosis, ALS, cerebral ischemia, and cardiovascular disease are endowed with an inflammatory component. The function of SK/K_Ca2 channel in stroke and Alzheimer’s disease was recently reviewed by Kuiper et al. (2012) and on atherosclerosis and cardiovascular diseases by Wulff and colleagues (Wulff et al., 2007; Köhler et al., 2010). Neurodegenerative diseases triggered by neuronal hyperexcitability, progressive dysregulated Ca²⁺ homeostasis, and excitotoxic neuronal death could benefit from small molecules that enhance SK/K_Ca2 channel activity (Kuiper et al., 2012). Other reviews present data on opening of endothelial K_Ca3.1/K_Ca2.3 channels, which stimulate endothelium-derived-hyperpolarizing-factor (EDHF)-mediated arteriolar dilation (Brähler et al., 2009) and lower blood pressure (Wulff et al., 2007; Köhler et al., 2010). On the other hand, inhibition of smooth muscle IK/K_Ca3.1 channels is considered for the treatment of pathological vascular remodeling and sickle cell anemia, since IK/K_Ca3.1 channel inhibition has particular beneficial effects in restenosis disease, atherosclerosis, and autoimmune encephalomyelitis (Wulff et al., 2007; Köhler et al., 2010).

Further, potassium IK1/SK4/K_Ca3.1 channels are also under intense investigation because of their high potential in therapeutic drug development for various pathophysiological conditions, including sickle cell anemia, pancreatic cancer, arterial restenosis, immune diseases, and CNS inflammation (Jensen et al., 2002; Köhler et al., 2003; Wulff et al., 2003; Jager et al., 2004). In particular, IK/K_Ca3.1 channels are highly expressed in murine microglial cells (Khanna et al., 2001) and are implicated in the production of reactive oxygen species, nitric oxide as well as peroxynitrite and protein tyrosine nitration (Skaper, 2011). Increasing evidence for beneficial effects of IK/K_Ca3.1 channel inhibition is mainly derived from studies using the selective antagonist triarylmethane-34 (TRAM-34), which does not exert any action on KCNN1-3/SK1-3/K_Ca2.1-K_Ca2.3 channels (Wulff et al., 2000). Interestingly, TRAM-34 reduces the neurotoxicity mediated by LPS-activated rat primary microglia, and this effect is associated with diminished iNOS expression and reduced caspase 3 activation (Kaushal et al., 2007). TRAM-34 also reduced the degeneration of retinal ganglion cells after optic nerve transection in adult female Sprague Dawley rats (Kaushal et al., 2007). It improved locomotor function, reduced the secretion of TNF-α and interleukin-1β, and diminished the expression of iNOS in a rodent model of spinal cord injury (Bouhy et al., 2011). In a rat model of ischemia/reperfusion stroke, TRAM-34 reduced infarct area by ≈50% as determined by hematoxylin and eosin staining and improved neurological deficits related to the secondary inflammatory damage (Chen et al., 2011).

Neuroinflammation and dysfunction of dopaminergic midbrain neurons have been implicated in the etiology of Parkinson’s disease (Qian et al., 2010; Whitton, 2010). Low-level activity of dopaminergic neurons and alterations of dopamine release have been associated with impairment in voluntary movements, working memory, and reward-based learning (Dunnett and Bjorklund, 1999; Spanagel and Weiss, 1999; Svensson, 2000). Therefore, it is of paramount importance to identify molecular mechanisms underlying dopaminergic activity and neurotransmitter release. During early postnatal development, dopaminergic neurons display anomalous firing patterns and exhibit spontaneous miniature hyperpolarizations, which are not present in adults (Cui et al., 2004). These spontaneous hyperpolarizations exhibit outward currents and depend on SK/K_Ca2 channel regulation, T-type Ca²⁺ channel activation, and RyR-dependent Ca²⁺-induced Ca²⁺ release in mouse and rat midbrain areas (Wolfart et al., 2001; Cui et al., 2004). In vivo recordings demonstrated that adult rat dopaminergic neurons exhibit either a single-spike pacemaker in a burst firing pattern or show irregular firing patterns (Wilson et al., 1977; Grace and Bunney, 1984), while in vitro recordings in rat dopamine neurons demonstrated a regular, low-frequency pacemaker activity (Grace and Onn, 1989). These discrepancies between in vitro and in vivo recordings reside in a particular type of synaptic activity able to switch dopaminergic neurons into burst firing (Cui et al., 2004).

SK/K_Ca2 channels are emerging candidates to control NMDAR activation (Ping and Shepard, 1996), GABA receptor-mediating inhibitory activities (Yanovsky et al., 2005) and postsynaptic conductances in dopaminergic neurons. In fact, a subtype of SK/K_Ca2 channels, SK3/K_Ca2.3 subtype was shown to be expressed in mouse, rat, and guinea pig dopaminergic neurons (Wolfart et al., 2001; Bosch et al., 2002; Sarpal et al., 2004; Benítez et al., 2011). The function of SK3/K_Ca2.3 channels was addressed in mouse dopaminergic neurons of the substantia nigra, where they regulate the frequency and precision of pacemaker spiking (Wolfart et al., 2001). However, SK3/K_Ca2.3 channels were not found in a subpopulation of mouse dopaminergic neurons in the ventral tegmental area (Wolfart et al., 2001), suggesting that these significant differences in the density of apamin-binding sites in dopaminergic neurons might be responsible for the functional differences between ventral tegmental area (A10) and substantia nigra (A9; Grenhoff et al., 1988). Recently, immune-electron microscopy established also the presence of SK2/K_Ca2.2 channel subtype in mouse dopaminergic neurons (Deignan et al., 2012). SK2/K_Ca2.2 channels are expressed exclusively in the dendrites of dopaminergic neurons, while SK3/K_Ca2.3 channels are expressed in the soma and, to a lesser extent, in the dendritic neuronal network. To gain further knowledge of the precise function of SK/K_Ca2 channels in dopaminergic neurons, experiments performed in subtype specific null mice have demonstrated that SK2/K_Ca2.2-containing channels are responsible for the precision of action potential timing, while SK3/K_Ca2.3-containing channels contribute to action potential frequencies (Deignan et al., 2012). Indeed, modulation of SK/K_Ca2 channels was shown to regulate the excitability of rat midbrain neurons (Ji et al., 2009). Positive SK/K_Ca2 channel modulation using a non-specific SK/K_Ca2 channel subtype compound, NS309 (Strøbaek et al., 2004) decreased the responsiveness of rat dopaminergic neurons to depolarizing currents, enhanced spike frequency adaptation, and slowed spontaneous firing, due to an increase in the amplitude and duration of AHP (Ji et al., 2009).

Further, CyPPA, a positive modulator of SK2/K_Ca2.2 and SK3/K_Ca2.3 channel subtypes (Hougaard et al., 2007), decreases spontaneous firing rate and increases the duration of the apamin-sensitive AHP, causing an activity-dependent inhibition of current-evoked action potentials in both mouse and rat midbrain slices via SK3/K_Ca2.3 channel activation (Herrik et al., 2012). Although CyPPA repressed dopamine release in a concentration-dependent manner in vivo systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice (Herrik et al., 2012). In vitro studies further demonstrated that CyPPA prevented neuronal loss in an AMPA-dependent toxicity model in rat dopaminergic neurons (Benítez et al., 2011). In contrast, negative pharmacological modulation by NS8593 (Strøbaek et al., 2006), a non-specific SK/K_Ca2 channel subtype compound increased rat dopaminergic excitability, induced an irregular pacemaker and bursting discharge (Ji et al., 2009) and reduced the number of rat dopaminergic neurons in a dose-dependent manner (Benítez et al., 2011).

Taken together, modulation of SK/K_Ca2 channels in dopaminergic neurons regulates neuronal excitability, survival, and neurotransmitter release, making them suitable candidates for therapeutic intervention in pathological conditions related to dopaminergic dysfunction, such as Parkinson’s disease.

Disturbed Ca²⁺ homeostasis is one of the major causes of delayed cell death and infarct development after acute brain damage, e.g., after cerebral ischemia. Consequently, reducing intracellular [Ca²⁺]_i levels by blocking NMDA receptors has been widely investigated in experimental and clinical stroke studies. However, inhibitors of NMDA receptors largely failed in clinical studies and, therefore, novel strategies controlling [Ca²⁺]_i homeostasis are warranted for the development of effective therapies. An alternative approach avoiding direct NMDA receptor targeting would be to modulate [Ca²⁺]_i homeostasis indirectly via [Ca²⁺]_i sensors, such as K_Ca channels. Earlier studies showed that pyramidal cells from the CA3 area of the rat hippocampus respond to chemical-induced ischemia with an initial transient hyperpolarization that is responsible for delayed neuroprotective effects (Tanabe et al., 1999). A potential neuroprotective role for SK/K_Ca2 channels was identified when apamin-sensitive SK/K_Ca2 conductance channels were activated and generated a pronounced outward current in response to brief ischemia in rat hippocampal organotypic slice cultures (Tanabe et al., 1999). Indeed, activation of SK2/K_Ca2.2 channels by NS309 or 1-EBIO positive modulators decreased brain damage area (Allen et al., 2011; Dolga et al., 2011) and also regulated calcium homeostasis (Dolga et al., 2011). In addition, SK2/K_Ca2.2 channel activation is required for neuroprotection in neurons against glutamate-induced excitotoxicity and also in vivo in a mouse model of middle cerebral artery occlusion (MCAo; Allen et al., 2011; Dolga et al., 2011).

Neuroinflammation is a critical component for the initiation and progression of several neurodegenerative pathologies, such as cerebral ischemia, schizophrenia, Parkinson’s, and Alzheimer’s diseases. Potential therapeutic approaches directed against both inflammation and neuronal degeneration might benefit from modulation of SK/IK/K_Ca channels since SK/K_Ca2 channel activity elicits a dual mechanism of action with direct protective effects in neuronal cells and inhibition of inflammatory activities in microglial cells. However, the role of SK/IK/K_Ca channels in microglial activity and maintenance needs further in depth investigation in order to reveal the culpable molecular mechanisms. It is of interest to determine whether SK/IK/K_Ca channels are endowed with similar characteristics among different species, whether their activity alters during aging or during the progression of neurodegeneration, and whether modulating SK/IK/K_Ca channel activity can limit neurodegeneration and related neuroinflammation. Altogether, the hitherto accumulated evidence exposes modulation of SK/IK/K_Ca channel functions as potential target in neurodegenerative diseases where inflammatory processes significantly contribute to the progress of neuronal dysfunction.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.