While most central nervous system (CNS) neurons receive the majority of their input through direct synaptic connections, there is evidence suggesting that they are in fact susceptible to modulation by changes in extracellular ionic composition during both physiological and pathophysiological conditions. In many regions of the CNS, there exists an identified extracellular receptor with the ability to sense levels of cations, most notably calcium. Here we report that activation of this calcium receptor (CaR) in neurons of the subfornical organ (SFO), a forebrain circumventricular structure, results in profound effects on neuronal excitability through metabotropic actions on a non-selective cation channel. Activation of the CaR by NPS R-467, an allosteric agonist of the CaR, evoked depolarizing plateau potentials ranging in duration from 5 to 30 s. Similarly, 5 mm CaCl2 caused depolarization and increased action potential frequency. NPS R-467 was found to activate a non-selective cation channel with a reversal potential of −48 ± 4 mV, and a slope conductance of 2.54 ± 11 nS. This current could also be elicted by spermine, a known agonist of the CaR. CaR-mediated activation of this channel was dependent upon both G proteins and intracellular Ca2+ signalling, as disruption of these pathways through inclusion of guanosine 5′-O-(2-thiodiphosphate) (GDP-β-S) and 1,2-bis(2-aminophenoxy)ethane-N,N,N ′,N ′-tetraacetic acid (BAPTA), respectively, in the recording pipette prevented activation of the current. Microinjection of CaR agonists into the SFO of anaesthetized rats resulted in a significant, site-specific elevation of blood pressure (mean area under curve, 141 ± 50 mmHg.s). Together, these results indicate that the CaR can play an important role in transducing the effects of changes in the extracellular ionic composition, and that these effects have implications for the neural control of fluid balance.