The where and how of PIP regulation of cone photoreceptor CNG channels

403 C o m m e n t a r y In this issue, Dai et al. present an investigation of the biophysics of phosphatidylinositide (PIP) regulation of the cyclic-nucleotide gated (CNG) channels expressed in cone photoreceptors. Although PIPs facilitate or stabilize the activation of many other types of ion channels , they strongly inhibit the response to cAMP or cGMP (collectively, cNMP) of CNG channels. Previous studies have addressed the molecular basis for PIP regulation of the olfactory CNG channel but not for that of rod and cone CNG channels. From a myriad of potential mechanisms, the present study elegantly teased out two regulatory structural elements that are located in the N-and C-terminal regions of the cone CNG channel and identified a modulatory mechanism that involves complex intersubunit communications. In conjunction with earlier studies on PIP regulation of the olfactory CNG channel and related hyperpolarization-activated CNG (HCN) and HERG channels, the present study provides insights into the molecular mechanism and the physiological role of PIP regulation of CNG channels. Cyclic nucleotides act as second messengers inside of cells. In the olfactory and visual systems, exogenous stimuli, odorants or photons, respectively, activate G-protein coupled receptors (GPCRs), triggering signal transduction pathways that result in an increase in cAMP concentration in olfactory neurons or a decrease in cGMP concentration in photoreceptors. In both of these sensory systems, CNG channels transduce the signal encoded by the changes in intracellular cNMP into changes in the membrane excitability of the primary neurons. Molecular cloning has identified six major types of CNG channels, including three  subunits (A1, A2, and A3) that can themselves form functional channels and three  subunits (A4, B1, and B3) that share similar topology with the  subunits but which form functional channels only when coassembled with promote the proper trafficking of  subunits to their subcellular destination and fine tune channel sensitivity to cNMP and other regulators, including membrane potential, calmodulin, and PIPs. In both olfactory neu-rons and photoreceptors, homomeric ( subunit) channels that have been well-characterized in Xenopus laevis oocytes and HEK293 cells fail to traffic to the appropriate areas of cilia and outer segments, highlighting the importance of the modulatory  subunits as molecular chaperons in polarized membrane trafficking (Biel and Michalakis, 2007). Studies over the past 15 years have revealed that PIPs, which are low-abundance lipid molecules mainly distributed on the inner leaflet of the membrane, associate …