Urocortin (UCN), a newly isolated peptide related to hypothalamic corticotrophin releasing factor (CRF) family, had been reported to play biologically diverse roles in several systems such as cardiovascular, reproductive, appetite, stress, and inflammatory responses, etc. It was thought previously to be an endogenous agonist, producing the several actions previously attributed to CRF. But, recently, it was shown to directly reduce L-type calcium currents of acute isolated cardiac myocytes and T-type calcium currents in mouse spermatogenic cells via inhibiting calcium channel instead of binding first to its CRF-R-2 receptors. UCN could also reduce the intracellular calcium in vascular smooth muscle cells via inhibiting calcium channel directly. Furthermore, UCN could increase the gene expression of ATP-sensitive potassium channels (K-ATP) and activate sarcolemmal ATP-sensitive potassium current during normal or hypoxia, which could be inhibited by glibenclamide, a specific K-ATP blocker. This review will highlight the current novel findings on the ionic mechanisms by which UCN may exert its several actions. (c) 2005 Elsevier Inc. All rights reserved.