Residues in the cytoplasmic region of S6 that are potentially involved in S6/U-motif interactions. Images show the 3D structures of the U motif, the CTD, and the S6 inner helix of RyR2 (30). A, mutations that enhance the activity of RyR2, including Q4876A, V4880A, K4881A, and M4884A, are located on one side of the S6 helix that faces the U motif. B, mutations that suppress RyR2 activity are located on the opposite side of the S6 helix that faces the conduction pore. C, potential hydrophobic interactions among residues Val4880 in the S6 helix and Ile4173, Phe4174, and Val4177 in the U motif of the central domain (14, 30).