Apland J P, Helekar S A, Lebeda F J
Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Mol Chem Neuropathol. 1997 Aug;31(3):265-78. doi: 10.1007/BF02815129.
The effect of cyclic adenosine 3',5'-monophosphate (cAMP) on epileptiform activity in rat hippocampal slices was investigated. Bath-applied cAMP reversibly decreased the frequency of extracellularly recorded discharges in the CA3 subfield induced by bethanechol- or theophylline-containing solutions. Because cAMP was presumed to be relatively membrane impermeant, we developed and tested the hypothesis that this cAMP-mediated effect occurred extracellularly through the catabolic conversion of cAMP to 5'-AMP and, in turn, to adenosine, a known inhibitory neuromodulator. Three predictions derived from this catabolic hypothesis were tested. First, blockers of the enzymes involved were predicted to antagonize this effect of cAMP. In contrast, the coapplication of a cAMP-phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), or a 5'-nucleotidase inhibitor, adenosine 5'-[alpha, beta-methylene] diphosphate (AMP-CP), enhanced the cAMP-induced suppressive effect. Second, the nonhydrolyzable cAMP analogs, dibutyryl- and 8-bromo-cAMP, were predicted to be ineffective. Low concentrations (5-40 microM) of these two derivatives, however, also suppressed bethanechol-induced discharges, while, at a higher concentration (100 microM), both analogs increased discharge frequencies. Third, enzymatic catabolism of adenosine was predicted to antagonize cAMP's effect, but coapplying adenosine deaminase (10 U/mL) did not diminish this action. Because these data did not support the catabolic hypothesis, other, as yet undefined, mechanisms must be responsible for the discharge-suppressant effect of cAMP.
研究了环磷酸腺苷（cAMP）对大鼠海马脑片癫痫样活动的影响。浴用cAMP可使由含氨甲酰甲胆碱或茶碱的溶液诱导的CA3亚区细胞外记录放电频率可逆性降低。由于cAMP被认为相对难以透过细胞膜，我们提出并检验了这样一个假说，即这种由cAMP介导的效应是通过cAMP分解代谢转化为5'-AMP，进而转化为腺苷（一种已知的抑制性神经调质）在细胞外发生的。对由该分解代谢假说得出的三个预测进行了检验。首先，预测参与该过程的酶的抑制剂会拮抗cAMP的这种效应。相反，联合应用cAMP磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤（IBMX）或5'-核苷酸酶抑制剂腺苷5'-[α,β-亚甲基]二磷酸（AMP-CP），可增强cAMP诱导的抑制效应。其次，预测不可水解的cAMP类似物二丁酰cAMP和8-溴cAMP无效。然而，这两种衍生物的低浓度（5 - 40 microM）也能抑制氨甲酰甲胆碱诱导的放电，而在较高浓度（100 microM）时，两种类似物均增加放电频率。第三，预测腺苷的酶促分解代谢会拮抗cAMP的效应，但联合应用腺苷脱氨酶（10 U/mL）并未减弱这种作用。由于这些数据不支持分解代谢假说，cAMP的放电抑制效应必定是由其他尚未明确的机制所致。
