TY - JOUR

T1 - CALCINEURIN INHIBITS DESENSITIZATION OF CLONED RAT 5-HT(1C)RECEPTORS

AU - BODDEKE, HWGM

AU - HOFFMAN, BJ

AU - PALACIOS, JM

AU - HOYER, D

PY - 1993/9

Y1 - 1993/9

N2 - Functional responses to stimulation of rat 5-HT1C receptors expressed in A9 cells were studied using whole cell voltage clamp recording technique. Stimulation of 5-HT1C receptors with serotonin (5-HT) evoked calcium-dependent outward currents of 109 pA in cells clamped at -50 mV. Pretreatment with the protein kinase C (PKC) activator phorbol myristic acetate (PMA) reduced the 5-HT-induced current amplitude by 46% of the control value. Inclusion of inositol triphosphate (IP3) in the pipette solution induced an outward current of 84 pA. The IP3-induced response was not affected by 60 min pretreatment with PMA. In the presence of the PKC antagonist calphostin C, 60 min treatment with PMA (10(-6) mol/1) reduced the 5-HT response only by 8%. In cells preincubated with PMA, injection of the calcium/calmodulin dependent serine proteinphosphatase calcineurin gradually increased the 5-HT-induced responses by 34%. In A9 cells which were incubated 24 h with the 5-HT1C receptor agonist meta chlorophenylpiperazine hydrochloride (mCPP), 5-HT-induced responses were reduced by 23% of the vehicle pretreated control value. Injection of calcineurin in mCPP treated cells enhanced the 5-HT-induced response by 24%.The results suggest that in A9 cells rat 5-HT1c receptors are desensitized after phosphorylation by PKC. This desensitization can be counteracted by calcineurin-induced dephosphorylation.

AB - Functional responses to stimulation of rat 5-HT1C receptors expressed in A9 cells were studied using whole cell voltage clamp recording technique. Stimulation of 5-HT1C receptors with serotonin (5-HT) evoked calcium-dependent outward currents of 109 pA in cells clamped at -50 mV. Pretreatment with the protein kinase C (PKC) activator phorbol myristic acetate (PMA) reduced the 5-HT-induced current amplitude by 46% of the control value. Inclusion of inositol triphosphate (IP3) in the pipette solution induced an outward current of 84 pA. The IP3-induced response was not affected by 60 min pretreatment with PMA. In the presence of the PKC antagonist calphostin C, 60 min treatment with PMA (10(-6) mol/1) reduced the 5-HT response only by 8%. In cells preincubated with PMA, injection of the calcium/calmodulin dependent serine proteinphosphatase calcineurin gradually increased the 5-HT-induced responses by 34%. In A9 cells which were incubated 24 h with the 5-HT1C receptor agonist meta chlorophenylpiperazine hydrochloride (mCPP), 5-HT-induced responses were reduced by 23% of the vehicle pretreated control value. Injection of calcineurin in mCPP treated cells enhanced the 5-HT-induced response by 24%.The results suggest that in A9 cells rat 5-HT1c receptors are desensitized after phosphorylation by PKC. This desensitization can be counteracted by calcineurin-induced dephosphorylation.

KW - RAT 5-HT(1C)RECEPTORS

KW - A9-CELLS

KW - DESENSITIZATION

KW - CALCINEURIN

KW - PROTEIN-KINASE-C

KW - XENOPUS OOCYTES

KW - RECEPTORS

KW - RESPONSES

KW - BRAIN

KW - BETA

M3 - Article

VL - 348

SP - 221

EP - 224

JO - Naunyn-Schmiedebergs Archives of Pharmacology

JF - Naunyn-Schmiedebergs Archives of Pharmacology

SN - 0028-1298

IS - 3

ER -