We next investigated the functional consequences of dystroglycan silencing on GPCR-mediated mobilization of [Ca 2+ ] i in smooth muscle cells (Fig. 4G,H). Cells expressing non-coding control shRNA exhibited typical concentration-response characteristics. However, cells lacking -dystroglycan exhibited significant suppression in peak [Ca 2+ ] i induced with lower concentrations of MCh. Indeed, in -dystroglycan-silenced myocytes, there was a significant reduction in the sensitivity to MCh (EC50 Control 50.3±14 nM versus EC50 shRNAi 220±24 nM; P<0.01). By contrast, and consistent with previous studies in which caveolin-1 expression was silenced (Gosens et al., 2007b), peak [Ca 2+ ] i induced with maximum concentrations of MCh were unaffected. Collectively, these **data** demonstrate that the requirement of -dystroglycan for caveolae integrity is a crucial determinant of the spatial profile of proximal signaling effectors, which has important consequences on the initiation of contraction by physiologically relevant agonists.