Specific involvement of Ca(2+)-calmodulin kinase II in cholinergic modulation of neuronal responsiveness.
1. Muscarinic agonists when applied in the hippocampus at low concentrations suppress intrinsic controls on neuronal excitability through the block of Ca(2+)-activated K conductance(s), gK (Ca), underlying the adaptation of firing and slow afterhyperpolarization (sAHP) in CA1 and CA3 neurons. Carbachol, for example, is effective at 0.1-0.3 microM suggesting activation of a relatively high-affinity receptor. 2. We have examined the mechanism of this action by using a new, highly specific, peptide inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) as well as other kinase inhibitors and show that the muscarinic block of gK (Ca) relies on CaMKII activation in both CA1 and CA3 neurons. Thus phosphorylation of these channels or of an intermediary protein causes the channels to remain closed in the presence of Ca2+ and depolarization. 3. The very similar electrophysiological effects of serotonergic and glutamatergic agonists are mediated either through other kinases or by entirely different processes. 4. Block of intrinsic phosphatase activity by okadaic acid also reduced adaptation and sAHP, and muscarinic agonists had no further effect on these quantities. 5. The removal of presynaptic cholinergic inputs to the hippocampus in animals has a deleterious effect on the performance of tasks requiring spatial memory and is also implicated as a cause of cognitive disorders in humans. By increasing Ca2+ accumulation during electrical activity and promoting CaMKII activity, muscarinic input provides parallel reinforcing pathways for the induction of long-term potentiation, an important cellular memory mechanism. This suggests a possible link between behavioral and cellular approaches to the analysis of learning and memory.
Müller
W
W
Roche Institute of Molecular Biology, Department of Neurosciences, Roche Research Center, Nutley, New Jersey 07110.
Petrozzino
J J
JJ
Griffith
L C
LC
Danho
W
W
Connor
J A
JA
D000222:Adaptation, Physiological / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002217:Carbachol / Q000494:pharmacology; D004594:Electrophysiology; D004789:Enzyme Activation; D004988:Ethers, Cyclic / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019319:Okadaic Acid; D010275:Parasympathetic Nervous System / Q000201:enzymology / Q000502:physiology*; D010276:Parasympatholytics / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*
D004988:Ethers, Cyclic; D010276:Parasympatholytics; D010455:Peptides; D047428:Protein Kinase Inhibitors; D019319:Okadaic Acid; D002217:Carbachol; D011494:Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases