Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease - PubMed (original) (raw)

Figure 2. Structural insights into gating and the formation of a macromolecular GIRK signaling complex

A, A structure (ribbon model superimposed with space filled model) of the Kirbac1.3/GIRK1 chimeric channel is shown in a typical lipid bilayer (‘out’: extracellular) This structure contains the cytoplasmic domains (N- and C-termini) of GIRK1, and the transmembrane domains (M1, M2) and pore region of the bacterial inward rectifier (Kirbac1.3) channel (PDB:2QKS). The structure of the GIRK1 cytoplasmic domain in this full-length chimeric protein is similar to those of other inward rectifiers -. The K+ selectivity filter is the site of the weaver mutation,,. The regions implicated in Na+ and PIP2 association are shown-,,. Two channel gates formed by the M2 transmembrane domain and cytoplasmic G-loop form a physical barrier to ion permeation,,,-. Note the constriction formed by the G-loop gate. B, Modulation sites are shown from a side-view perspective in two adjacent subunits. The regions implicated in Gβγ activation (light and dark green β-strands; H69, L273 and L344: Yellow),-, Gαi/o association (red and pink β-strands, G318, C321 and A323 - blue),,, and ethanol-dependent activation (N-terminus:blue; βD-βE sheet: yellow; βL-βM sheet: green; L257:red) are shown. The sites are mapped on structure of GIRK2 (PDB:2E4F) C), Schematic shows a macromolecular signaling complex that contains a GPCR, which couples to PTX-sensitive Gαi/o G proteins, a GIRK channel, an RGS protein, SNX27, and possibly PSD95. Gβγ opens GIRK channels (+). Modulators of GIRK channels are also shown, including tyrosine kinase, CaMKII kinase, PKA/PKC kinases, and PP1 phosphatase-,,,. A second GPCR that couples to the Gq pathway is shown. Activation of this pathway stimulates PLC, which leads to activation of PKC, and depletion of PIP2, both of which reduce (−) GIRK channel activity,,. Pertussis toxin (PTX) inhibits (−) activation of GIRK channels through Gαi/o G proteins.