Theoretical analyses of the functioning of the high- and low- K m cyclic nucleotide phosphodiesterases in the regulation of the concentration of adenosine 3′,5′-cyclic monophosphate in animal cells

Abstract

The concentration of cyclic AMP in a cell is determined by the activities of three enzymes: adenylate cyclase; low- K m phosphodiesterase, and high- K m phosphodiesterase. Analysis of the properties of this system has been undertaken. When the system is treated as three soluble enzymes, the steady state concentration of cyclic AMP in the cell is seen to be relatively insensitive to the activity of high- K m diesterase, which is present in larger amounts than can be readily explained. By numerical simulation of a more realistic model which treats adenylate cyclase and low- K m diesterase as enzymes bound to the plasma membrane, it is demonstrated that the system can exhibit greater flexibility. The content of high- K m diesterase is shown to be sufficient to generate a concentration gradient of cyclic AMP in a cell where adenylate cyclase is on the plasma membrane. This lowers the steady state concentration of cyclic AMP. Although it is normally ineffective at controlling the cyclic AMP concentration near the membrane, the high- K m enzyme can be as effective as the low- K m diesterase at regulating the level further inside the cell. The rate of approach to a new steady state after modulation of cyclase activity is also increased by high- K m diesterase. Although only a single pool of cyclic AMP is assumed, differences are predicted between cyclic-AMP dependent processes at the plasma membrane compared with the interior of the cell. On or near the membrane, modulation of only the cyclase or low- K m diesterase can exert control on the process, and the rate of response will be faster than the rate of change of the cellular content of cyclic AMP. Nervous tissue may be an exception, where the high- K m diesterase does control the concentration near the membrane effectively.