Kv7 channels (KCNQ) represent a family of voltage-gated K+ channels, which plays a prominent role in brain and cardiac excitability. Their physiological importance is underscored by the existence of mutations in human Kv7 genes, leading to severe cardiovascular and neurological disorders such as the cardiac arrhythmias and neonatal epilepsy. In the heart, the assembly of Kv7.1 with KCNE1 produces the IKS potassium current that is crucial for the late repolarization of the cardiac action potential. Mutations in either Kv7.1 or KCNE1 genes produce the long QT or short QT syndromes, which are genetically heterogeneous cardiovascular diseases, characterized by ventricular or atrial arrhythmias. The scaffolding A-kinase anchoring protein Yotiao (AKAP9) brings together PKA, PP1, PDE4D3, AC9, and the IKS channel complex to achieve regulation following β adrenergic stimulation. Kv7 channels exhibit some structural and functional features that are distinct from other Kv channels. Notably, the Kv7 family lacks the T1 tetramerization domain and it does not associate with the Kvβ subunit. Rather, it has a large intracellular C-terminal (CT) domain, ranging from 320 to 500 residues in size, bound constitutively to calmodulin. This domain is responsible for channel tetramerization, proper channel trafficking, and gating properties. Here we provide a brief overview of current insights and yet unsettled issues about the gated motions and assembly modalities of the IKS potassium channel complex. Proximal helices A and B form the site for calmodulin (CaM) binding, while distal coiled-coil helices C and D are important for channel tetrameric assembly and protein interactions. We studied the interactions and voltage-dependent motions of IKS channel intra-cellular domains, using fluorescence resonance energy transfer combined with voltage-clamp recording and in-vitro binding of purified proteins. The results indicate that the KCNE1 distal C-terminus interacts with the coiled-coil helix C of the Kv7.1 tetramerization domain. This association is important for IKS channel assembly rules as underscored by Kv7.1 current inhibition produced by a dominant-negative C-terminal domain. Upon channel opening, the C-termini of Kv7.1 and KCNE1 come close together. Co-expression of Kv7.1 with the KCNE1 long QT mutant D76N abolished the K+ currents and gated motions. Thus, during channel gating KCNE1 is not static. Instead, the C-termini of both subunits experience molecular motions, which are disrupted by the D76N causing disease mutation. We investigated the structure of the membrane proximal CT module in complex with CaM by x-ray crystallography. The results show that CaM intimately hugs a two helical-bundle. Biochemical data, structure-based mutagenesis of this module in the context of concatemeric channels and functional analysis lead us to conclude that one CaM binds to one individual protomer, without crosslinking subunits and that this configuration is required for proper channel expression. Molecular modeling of the CT/CaM complex in conjunction with small-angle X-ray scattering and electrophysiology suggest that the membrane proximal region, with a rigid lever arm is a critical gating module. We examined the effect of long QT mutations located at the C-terminal interface of the two subunits. Our results suggest that the distal KCNE1 C-terminus, probably via its interaction with the coiled-coil helix C, is a crucial determinant for the functional modulation of Kv7.1 by Yotiao-mediated PKA phosphorylation.