Renin is produced, stored and released from juxtaglomerular (JG) cells, which are modified smooth muscle cells located in the lamina media of the afferent arteriole at the site of entrance to the glomerulus. Using whole-cell patch clamp on JG-cells in isolated mouse afferent arterioles Kurtz & Penner (5) showed that JG-cells were nearly electrically silent at holding potentials between -50 and -10 mV, while there were outward K-currents at positive potentials and inward K-currents at negative potentials. They further identified a high density of calcium-activated chloride channels. We have isolated mouse and rat JG-cells ad modum (1) and studied them with whole-cell patch clamp technique in order to delineate the ion channels responsible for their electrical behaviour (2, 3, 4). Single JG cells displayed marked outward current at positive membrane potentials. Tetraethylammonium inhibited 4/5 of the outward current, suggesting that K+ channels carry most of the current. Inhibition of Kv channels with 4-AP blocked 1/5 of the current. Inhibition of BKCa channels with iberiotoxin blocked 4/5 of the outward current. Furthermore, chelation of intracellular calcium with EGTA abolished the outward current. Thus, the outward potassium current is mainly carried through BKCa channels, the presence of which was confirmed with immunocytochemistry. Cyclic AMP increases outward currents in JG-cells (2, 3), and these currents were blocked by BKCa-specific inhibitors, suggesting that the BKCa splice variant in JG cells is the cAMP-stimulated ZERO variant (KCa1.1, ZERO variant). This was confirmed by RT-PCR. Activation of BKCa with cAMP led to a 16 mV hyperpolarisation of membrane potential while inhibition of the channels caused a 16 mV depolarisation. Thus, the BKCa channels influence the resting membrane potential of JG cells. In spite of this, inhibition of the BKCa channels had no effect on cAMP-induced renin secretion, showing that hyperpolarisation is not a prerequisite for renin secretion. Mouse JG-cells display inward rectification of current at negative potentials, and the current has functional characteristics as the KIR (2, 5). By contrast, inward rectification was not observed in any of 326 rat JG-cells (4). At variance with a number of functional studies, we found that JG-cells are endowed with high-voltage activated Ca channels (Cav) that are activated at a membrane potential of -20 mV and display maximal activation at +10- +20 mV (4). The current was blocked by the L-type channel blocker calciseptine and its expression of Cav 1.2 was confirmed by RT-PCR analysis. Immunostaining of kidney cryosections and of JG-cells showed colocalisation of renin and Cav. To examine the functional role of Cav we measured renin secretion (change in membrane capacitance) at different holding potentials. In unstimulated JG-cells the membrane capacitance was unaffected by holding potentials from -30 mV to +10 mV. Cyclic AMP increased membrane capacitance about 10% at -30 mV, but had no effect at +10 mV where Cav are activated. The inhibition of cAMP effects at +10 mV was abolished by calciseptine, indicating that the activated L-type Cav were responsible for the inhibition of cAMP-stimulated renin release. Thus, at depolarised potentials calcium influx through Cav inhibits renin release. In conclusion, cAMP-activated BKCa. are involved in setting the resting membrane potential of juxtaglomerular cells. They are responsible for the major part of the outward current observed at depolarised membrane potentials, and they are responsible for the hyperpolarisation observed after cAMP stimulation. Rat juxtaglomerular cells express L-type voltage-dependent calcium channels (Cav 1.2) and activation of these channels inhibits cAMP-induced renin secretion. Cyclic AMP-induced stimulation of renin secretion may be protected against activation of L-type Cav by the hyperpolarisation induced by opening of BKCa.