, 2013). These examples illustrate how cargo receptors and dedicated auxiliary subunits may regulate channel traffic, thereby controlling channel density and composition. As channels assemble in the ER and traffic through the secretory pathway and endosomal pathway, they are exposed to different chaperones

and modifying enzymes as well as different pHs ranging from pH 7.2 in the ER lumen, to pH 6.0–6.7 in the Golgi, and pH 5.5 in secretory vesicles (Mindell, 2012 and Stauber and Jentsch, 2013). Retrieval of channels from the cell surface for recycling or degradation also takes channels from a neutral to a low pH environment on the extracellular/luminal side. The sensitivity of various channels to pH on the extracellular and luminal side of the membrane may be one of the mechanisms to modulate channel

activity in different intracellular compartments and seems to be a fundamental Vorinostat molecular weight property of the channel life Selleck Birinapant cycle that deserves increased scrutiny. In the final paragraphs of this Perspective, we offer some thoughts for key challenges that remain for the field. Since the first characterization of the squid axonal sodium and potassium conductances and their voltage dependence 60 years ago by Hodgkin and Huxley (Hodgkin and Huxley, 1952), a desire to understand the nature and mechanics of ion channels has driven the field to devise novel approaches, such as the patch clamp (Hamill et al., 1981), and to harness challenging technologies including crystallography and real-time monitoring of channel conformational changes, in order to study how ion channels work and how they mediate neuronal signaling. These studies have uncovered Terminal deoxynucleotidyl transferase the molecular motions of sensing and gating most completely in voltage-gated (Chowdhury and Chanda, 2012, Tombola et al.,

2006 and Vargas et al., 2012), acetylcholine-gated (Changeux, 2012, Corringer et al., 2012 and Unwin, 2013), and glutamate-gated (Mayer, 2011 and Paoletti et al., 2013) channels and revealed the modular construction of many channel types, both within the membrane portions (Minor, 2006 and Yu and Catterall, 2004) and in the extramembranous parts (Mayer, 2011 and Minor, 2007). Understanding how such multicomponent devices act to integrate input signals that regulate the basic function of opening a hole for ions to pass remains a major challenge. There are many channel families in which the gating mechanisms are still very obscure, including thermosensation by TRP channels (Nilius and Owsianik, 2011 and Ramsey et al., 2006a), mechanosensation by the TRP channel NOMPC (Yan et al., 2013) and Piezo channels (Coste et al., 2012 and Kim et al., 2012), and the gating of CRAC channels via formation of multiprotein complexes that involve both plasma and intracellular membrane components (McNally and Prakriya, 2012).