The ion channel NOMPC (orange) is a transmembrane protein that is anchored to the neuron’s cytoskeleton (green circles), allowing it to detect mechanical force. This stimulates the pore of the channel (brown arrow) to open, leading to the generation of an electrical signal within the neuron. At the same time, the extracellular domain (ECD) of another transmembrane protein, the adhesion GPCR dCIRL, detects the mechanical force differently as a result of being anchored to the extracellular matrix (blue strings). Activation of dCIRL decreases the level of cAMP in the cell, possibly due to the activation of a G protein (Gαi) that inhibits the enzyme that makes cAMP (known as adenylate cyclase). Unidentified signaling components downstream of cAMP alter NOMPC activity to modulate the strength of the overall response. In this manner, both extracellular and intracellular views of the same stimulus are combined to precisely adjust the neuronal response. GAIN, GPCR autoproteolytic domain. 7TM: seven transmembrane domain.