Model for tuning phosphoinositide sensitivity of cone CNG channels via intersubunit interactions. Six scenarios here illustrate how proposed N–C interactions between channel subunits may control PIPn regulation. Two regulatory modules are located within the N- and C-terminal regions of CNGA3 subunits, respectively. These PIPn-regulation modules can be silenced (red) or activated (green) due to changes in intersubunit interactions. (i) One component involves the C-terminal region of CNGA3, which is necessary for a PIPn-dependent increase in cAMP efficacy. (ii and v) The other component, manifested as a decrease in apparent cGMP affinity, requires the N-terminal region of CNGA3 and is unmasked either by deletion of the C-terminal region (ii) or by assembly with CNGB3 subunits (v). (iii) PA-LP mutations in CNGA3 also alter N–C coupling, thereby activating the N module and silencing the C module. (iv) The PIPn-regulation competency of channels formed by A3//A3 N7R-A,613X tandem dimers supports an intersubunit N–C interaction. (vi) In addition, PIPn regulation of heteromeric CNGA3+CNGB3 channels depends on N and C regulatory modules in CNGA3.
