Archaeorhodopsin-3 (Arch) and

halorhodopsin (NpHR) are members of the opsin family used to silence neuronal activity (Chow et al., 2010 and Zhang et al., 2007). Illumination of Arch, a proton pump, for an extended period of time could result in intra- and Tariquidar solubility dmso extracellular pH disturbance, which could negatively impact on cell health (Han, 2012 and Okazaki et al., 2012). Activation of the chloride pump NpHR leads to accumulation of intracellular chloride ions and can compromise GABAA-receptor-mediated inhibition (Raimondo et al., 2012). In addition, continuous activation of Arch or NpHR is limited by its inactivation and potential photo damage, which is not ideal for studies, such as those researching epilepsy, in which it is important to maintain membrane hyperpolarization for a long period of time (Kokaia et al., 2013). Selleckchem Doxorubicin In contrast, PIRK is based on Kir2.1, an inward rectifying potassium channel whose native function is to regulate neuronal excitability (Bichet et al., 2003, Hibino et al., 2010 and Nichols and Lopatin, 1997). Through a small amount of outward K+ current, Kir2.1 can directly silence the electrical activity of neurons. In fact, ectopic expression of Kir channels has been used previously over the last decade to investigate the effect of neuronal excitability on circuit function (Burrone et al., 2002, Johns

et al., 1999, Nadeau et al., 2000 and Yu et al., 2004). By endowing Kir2.1 with photoresponsiveness in PIRK, we have provided

the ability to temporally control through light precision the activation of Kir2 channels. Another advantage PD184352 (CI-1040) of PIRK is that it functions like a binary switch, whereby a single light pulse can induce the lasting silencing effect on target neurons. Without the need to continuously deliver light through the optical fiber, this binary switch feature of PIRK is convenient for animal studies to mitigate potential interference of light or light devices on animal behavior and could, therefore, be useful for studying or treating intractable epilepsy, intractable pain, or muscle spasms. Moreover, PIRK channels may be utilized for studying a variety of physiological processes and diseases that directly involve Kir2.1 channels. For example, Kir2.1 function has been implicated in Andersen syndrome (Plaster et al., 2001), cardiac short QT syndrome (Priori et al., 2005), and osteoblastogenesis (Zaddam et al., 2012). PIRK is designed with a photoreleasable pore-blocking group. This “block-and-release” strategy may be generally applicable to other channels and receptors. For instance, G protein-gated Kir channels (Kir3 family), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and N-Methyl-D-aspartic acid receptors share similar pore topology with Kir2.1. By incorporating Cmn into pore residues in these proteins, one should be able to similarly install in light responsiveness to them for highly disciplined study of channel/receptor physiology.