<p>Hereditary defects in the function of the inwardly rectifying potassium channel Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreoretinal degeneration. However, this ion channel is widely expressed, and studies also suggest that Kir7.1 may be directly regulated in a G protein-independent manner by a GPCR, the melanocortin-4 receptor (MC4R), in specific hypothalamic neurons involved in energy homeostasis. To advance our understanding of this unusual direct regulation of an ion channel by a GPCR, it is important to characterize the structure and function of Kir7.1, and the Kir7.1-MC4R complex. Utilizing cryo-electron microscopy, we present structures of human Kir7.1 and demonstrate the structural basis for the blockade of the channel by a small molecule ML418. We show that channel blockade of Kir7.1 depolarizes MC4R neurons in a slice preparation of the paraventricular nucleus of the hypothalamus (PVH), and activates PVH neurons in vivo, inhibiting food intake and inducing weight loss. We further show that Kir7.1 and MC4R are in close association on the plasma membrane and characterize a fusion construct of MC4R and Kir7.1 that provides an experimental tool for study of Kir7.1 regulation by the MC4R.</p>