Abstract m 3 -Muscarinic cholinergic receptor (m 3 -AChR) and α 1 -adrenergic receptor (α 1 -AR) stimulation of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) hydrolysis (by a PIP 2 -specific phospholipase C, PLC) in rat parotid gland membranes is mediated via activation of α subunits of the G q/11 family of G-proteins. This study examines m 3 -AChR and α 1 -AR stimulation of PIP 2 hydrolysis in membranes isolated from parotid glands of old (24 months) and young (3 months) rats (old and young rat membranes). Old rat membranes exhibited reduced stimulation of PIP 2 hydrolysis in response to the addition of guanosine-5′- O -(3-thiotrisphosphate) (GTPγS) alone or GTPγS plus either carbachol (m 3 -AChR agonist) or epinephrine (α 1 -AR agonist). This reduction in receptor-stimulated PIP 2 hydrolysis was not due to a decrease in PLC activity per se since cholate-solubilized PLC activity was similar in old and young rat membranes. Additionally, these membranes exhibited comparable, immunologically detectable, levels of PLCβ 3 , Gα q/11 , and G β . In the presence of 10 μM AlCl 3 and 10 mM NaF, stimulation of PIP 2 hydrolysis in both old and young rat membranes was similar. Preincubation of membranes from old rats with GTPγS induced a time-dependent increase in the rate of PIP 2 hydrolysis and, with 20 min preincubation, the rates of hydrolysis in old and young rat membranes were not statistically different. In aggregate, these data indicate that there is a defect in the activation of G αq/11 in parotid gland membranes from old rats.