A model depicting distance constraints on activation of TRPV4 channels by AKAP150-bound PKCα in vascular smooth muscle cells. Our in vitro and in silico data suggest that in arterial smooth muscle, the radius of action of an activated PKCα is ∼200 nm. In male and female pial myocytes as well as male parenchymal myocytes, the level of expression of AKAP150/PKCα complexes is sufficiently high to locate many of these complexes within 200 nm of TRPV4 channels. Accordingly, TRPV4 activity in these cells is relatively high. In cells such as mesenteric myocytes, which express relatively low levels of AKAP150 and/or TRPV4, the density of these proteins in the sarcolemma is low. This results in an increase in the mean distance between AKAP150 and/or TRPV4 clusters. In cells (e.g., female parenchymal myocytes and male and female mesenteric myocytes) where the distance between these clusters is >200 nm, TRPV4 channel activity is undetectably low.