CORTISTATIN INCREASE OF A POTASSIUM CONDUCTANCE IN RAT LOCUS-COERULEUS IN-VITRO

1 In this study we examined the effects of cortistatin, a putative end ogenous ligand for somatostatin (SRIF) receptors, on the membrane prop erties of rat locus coeruleus (LC) neurones in vitro, by use of intrac ellular and whole cell patch clamp recording. We have compared the act ions of cortistatin with those of SRIF and the SRIF analogue D-Phe-Cys -Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). 2 When LC neurones were voltage clamped to -60 mV, application of cortistatin caused an outward curre nt in all cells examined (n=44), with a pEC(50) of 6.62. SRIF also cau sed an outward current in all cells examined (n=43), with a PEC50 Of 6 .93. 3 The outward currents caused by cortistatin in 2.5 mM extracellu lar K+ reversed polarity at -106 mV, very close to the predicted K+ re versal potential of -105 mV. Increasing extracellular K+ to 10.5 mM re sulted in a shift of the reversal potential of +38 mV, a shift consist ent with a K+ conductance. The conductance activated by cortistatin sh owed mild inward rectification. 4 Continuous application of a high con centration of SRIF (1 mu M) resulted in a decrease of the outward curr ent to a steady level of 49% of the maximum response, with a t(1/2) of 131 s. Application of a high concentration of cortistatin (3 mu M) du ring the desensitized portion of the SRIF response did not result in a ny further outward current. Continuous application of a high concentra tion of cortistatin (10 mu M) resulted in a decrease of the outward cu rrent to a steady level of 42% of the maximum response with a t(1/2) o f 114 s. Application of a high concentration of SRIF (3 mu M) during t he desensitized portion of the cortistatin response produced only a sm all outward current. 5 Continuous application of cortistatin (3 mu M) also resulted in a decrease of the outward current (by 43%, t(1/2) of 136 s) and application of a high concentration of CTOP (10 mu M) durin g the desensitized portion of the cortistatin response did not produce any outward current. Continuous application of a high concentration o f CTOP (10 mu M) resulted in a decrease of the outward current to a st eady level of 70% of the maximum response with a t(1/2) of 143 s. Appl ication of a high concentration of cortistatin (3 mu M) during the des ensitized portion of the CTOP response did not result in any further o utward current.6 The actions of cortistatin (300 nM-10 mu M) were not affected by the opioid antagonist naloxone (10 mu M). Application of m et-enkephalin during the desensitized portion of the response to a hig h concentration of cortistatin (3 mu M) produced an outward current si milar to that produced by metenkephalin application alone. 7 Thus cort istatin efficaciously activates an inwardly rectifying K+ conductance in LC neurones. These actions appear to be mediated by a population of SRIF receptors, at which CTOP is also an agonist. Cortistatin does no t appear to be a ligand for mu-opioid receptors in rat LC neurons.