L-AP4 inhibition of depolarization-evoked cGMP formation in rat cerebellum.
The effects of the group III mGluR agonist, L-2-amino-4-phosphonobutyrate (L-AP4), on depolarization-stimulated cGMP levels in adult rat cerebellar slices were determined. L-AP4 elicited a concentration-dependent, complete inhibition of cGMP formation stimulated by 4-aminopyridine (4-AP; 1 mM), yielding an IC50 value of 4.2 +/- 1.6 microM (n = 3). The 4-AP response was also reduced by the P-type Ca2+ channel toxins omega-conotoxin MVIIC (3 microM; 39 +/- 7% inhibition) and omega-Agatoxin IVA (30 nM; 53 +/- 4%), and was abolished in the absence of Ca2+ or in the presence of Co2+. The inhibitions of the 4-AP cGMP response by 10 microM L-AP4 and 30 nM omega-Agatoxin IVA were not additive, indicating that part of the actions of L-AP4 in the cerebellum involves the modulation of P-type Ca2+ channels.
Cartmell
J
J
Pharma Division Preclinical Research, F. Hoffmann-La Roche, Basel, Switzerland. jayne.cartmell@roche.com
Kemp
J A
JA
Mutel
V
V
D015761:4-Aminopyridine / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D006224:Cricetinae; D006152:Cyclic GMP / Q000096:biosynthesis*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins
D000613:Aminobutyrates; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D010455:Peptides; D013111:Spider Venoms; D014665:Vasodilator Agents; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D009599:Nitroprusside; D015761:4-Aminopyridine; D006152:Cyclic GMP; C012729:2-amino-4-phosphonobutyric acid