Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons

Abstract

Aging impairs the function of the suprachiasmatic nucleus (SCN, the central mammalian clock), leading to a decline in the circadian rhythm of many physiological processes, including sleep-wake rhythms. Recent studies have found evidence of age-related changes in the circadian regulation of potassium currents; these changes presumably lead to a decrease in the SCN's electrical rhythm amplitude. Current through large-conductance Ca(2+)-activated K(+) (BK) channels promote rhythmicity in both SCN neuronal activity and behavior. In many neuron types, changes in BK activity are correlated with changes in intracellular Ca(2+) concentration ([Ca(2+)]i). We performed patch-clamp recordings of SCN neurons in aged mice and observed that the circadian modulation of BK channel activity was lost because of a reduction in BK currents during the night. This reduced current diminished the afterhyperpolarization, depolarized the resting membrane potential, widened the action potential, and increased [Ca(2+)]i. These data suggest that reduced BK current increases [Ca(2+)]i by altering the action potential waveform, possibly contributing to the observed age-related phenotype.

Modulation of BK Channel Function by Auxiliary Beta and Gamma Subunits

“…In central nervous system neurons, BK channels mediate the repolarization and fast afterhyperpolarization of action potentials (Shao, Halvorsrud, Borg-Graham, & Storm, 1999; Womack & Khodakhah, 2002), shape dendritic Ca 2+ spikes (Golding, Jung, Mickus, & Spruston, 1999), and regulate neurotransmitter release at presynaptic terminals (Hu et al, 2001; Raffaelli, Saviane, Mohajerani, Pedarzani, & Cherubini, 2004; Samengo, Curro, Barrese, Taglialatela, & Martire, 2014; Xu & Slaughter, 2005; see Chapter “BK Channels in Neurons” by Barth and Contet). Neuronal BK channels are involved in motor coordination (Sausbier et al, 2004), learning and memory (Matthews & Disterhoft, 2009; Springer, Burkett, & Schrader, 2014; Typlt et al, 2013; Ye, Jalini, Mylvaganam, & Carlen, 2010), the brain’s intrinsic rhythmicity of the circadian clock (Farajnia, Meijer, & Michel, 2015; Meredith et al, 2006; Montgomery, Whitt, Wright, Lai, & Meredith, 2013; Pitts, Ohta, & McMahon, 2006) and respiration (Onimaru, Ballanyi, & Homma, 2003; Zavala-Tecuapetla, Aguileta, Lopez-Guerrero, Gonzalez-Marin, & Pena, 2008; Zhao, Hulsmann, Winter, Dutschmann, & Richter, 2006), frequency tuning of the cochlear hair cell (Fettiplace & Fuchs, 1999), pain modulation (Cao, Chen, Li, & Pan, 2012; Chen, Cai, & Pan, 2009; Waxman & Zamponi, 2014; Zhang, Mok, Lee, Charbonnet, & Gold, 2012), and neuroprotection in pathological conditions (Mancini et al, 2014; Runden-Pran, Haug, Storm, & Ottersen, 2002; Shen, Kishimoto, Linden, & Sapirstein, 2007; Zhang, Xie, et al, 2009). Defects or dysregulation in human neuronal BK channels can cause epilepsy and paroxysmal dyskinesia (Brenner et al, 2005; Du et al, 2005) and are implicated in mental retardation (Deng et al, 2013; Higgins, Hao, Kosofsky, & Rajadhyaksha, 2008), autism (Laumonnier et al, 2006), and schizophrenia (Zhang, Li, Zhou, & Xing, 2006).…”

Should they team up to make your brain clock?

“…Indeed, under typical physiological conditions, opening of BK channels allows potassium ions to flow outside of the cell leading to membrane repolarization and fast afterhyperpolarization, thus controlling cellular excitability. These aspects are of direct relevance to a new study by Farajnia et al, 2015, reported in this issue of Neurobiology of Aging, on the role of BK channels in aging circadian clock neurons.…”

“…Indeed, under typical physiological conditions, opening of BK channels allows potassium ions to flow outside of the cell leading to membrane repolarization and fast afterhyperpolarization, thus controlling cellular excitability. These aspects are of direct relevance to a new study by Farajnia et al, 2015, reported in this issue of Neurobiology of Aging, on the role of BK channels in aging circadian clock neurons.Ó 2015 Elsevier Inc. All rights reserved.Large-conductance calcium (Ca 2þ )-activated potassium (K þ ) channels (BK channels) are important regulators of neuronal excitability in the mammalian nervous system. BK channels are activated by changes in membrane electrical potential and intracellular Ca 2þ concentration, and play a key role in shaping neuronal action potential.…”

“…Indeed, under typical physiological conditions, opening of BK channels allows potassium ions to flow outside of the cell leading to membrane repolarization and fast afterhyperpolarization, thus controlling cellular excitability. These aspects are of direct relevance to a new study by Farajnia et al (2015), reported in this issue of Neurobiology of Aging, on the role of BK channels in aging circadian clock neurons.The suprachiasmatic nucleus (SCN) in the hypothalamus is responsible for generating electrical and hormonal activities in a 24-hour cycle, which in turn contribute to the control of mammalian circadian rhythms. It was postulated that age-related change of circadian rhythms might be caused by alteration of the ionic conductances and membrane excitability of SCN neurons.…”

SGK3 Sensitivity of Large-Conductance Ca²⁺-Activated K⁺ Channel

“…They are involved in motor coordination [59], learning and memory [28,[60][61][62], circadian rhythm [63][64][65][66], regulation of respiration [67][68][69], hearing [70], and pain [71][72][73][74]. BK channels confer neuroprotection [75][76][77][78].…”