Homer proteins in Ca²⁺ signaling by excitable and non-excitable cells

Homers are scaffolding proteins that bind Ca²⁺ signaling proteins in cellular microdomains. The Homers participate in targeting and localization of Ca²⁺ signaling proteins in signaling complexes. However, recent work showed that the Homers are not passive scaffolding proteins, but rather they regulate the activity of several proteins within the Ca²⁺ signaling complex in an isoform-specific manner. Homer2 increases the GAP activity of RGS proteins and PLCβ that accelerate the GTPase activity of Gα subunits. Homer1 gates the activity of TRPC channels, controls the rates of their translocation and retrieval from the plasma membrane and mediates the conformational coupling between TRPC channels and IP₃Rs. Homer1 stimulates the activity of the cardiac and neuronal L-type Ca²⁺ channels Ca_v1.2 and Ca_v1.3. Homer1 also mediates the communication between the cardiac and smooth muscle ryanodine receptor RyR2 and Ca_v1.2 to regulate E-C coupling. In many cases the Homers function as a buffer to reduce the intensity of Ca²⁺ signaling and create a negative bias that can be reversed by the immediate early gene form of Homer1. Hence, the Homers should be viewed as the buffers of Ca²⁺ signaling that ensure a high spatial and temporal fidelity of the Ca²⁺ signaling and activation of downstream effects.