Hepatic receptors are normally exposed to discrete pulses of insulin and glucagon at intervals of 8 to 16 min. Using a multicolumn system for perifusing hepatocytes, we investigated the effect of this pattern on the normal processing of the insulin receptor. Surface-receptor binding was measured in acid-washed cells harvested from individual columns. The number of high-affinity surface receptors fell to a nadir 1 min after the end of a 3-min square-wave pulse of insulin. The maximum reduction reached 45% of baseline at amplitudes of 1000 μU/ml or above. The number of surface binding sites returned to baseline 15 min after the end of the pulse, but the affinity constant of the high-affinity receptor was unchanged. The reduction of surface binding was dose dependent, with an ED50, of 251 ± 34 μU/ml. Prolonging the pulse to 60 min did not affect the nadir or the rate of restoration of the surface-receptor population. The change in surface binding was reduced at 15°C and abolished at 4°C. After a pulse, the pattern of change was a period of rapid decline to a nadir (t1/2 ≤ 1 min) that persisted for 3–5 min, followed by restoration of surface binding that reached baseline in 10–15 min. This same pattern was present after six ED95 pulses delivered at intervals of 15 min. These data indicate that the internalization of hepatocyte surface receptors and their recycling and reinsertion into the plasma membrane can be entrained to pulses at the physiologic pulse frequency.

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