Abstract
Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (I-A) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of I-A. Specific activators of PKA produced a negative shift in voltage dependence of I-A, whereas PKA inhibitors produced a positive shift in I-A voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in I-A induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in I-A voltage dependence. This partial effect of PKA. inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of I-A.
| Original language | English |
|---|---|
| Pages (from-to) | 2081-2088 |
| Number of pages | 8 |
| Journal | Life sciences |
| Volume | 56 |
| Issue number | 23-24 |
| Publication status | Published - 5 May 1995 |
Keywords
- CANNABINOID
- RECEPTOR
- POTASSIUM CURRENT
- PROTEIN KINASE
- CAMP
- ADENYLATE-CYCLASE
- INHIBITION
- INACTIVATION
- CHANNELS
- CELLS