Catecholamine-stimulated cyclic GMP accumulation in the rat pineal: apparent presynaptic site of action.

O’Dea, Robert F.; Zatz, Martin

doi:10.1073/pnas.73.10.3398

Cited by 70 publications

(23 citation statements)

References 27 publications

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“…As indicated above, it has been thought that the cGMP response occurred to a large extent in nerve endings in the pineal gland, not in pinealocytes. The primary reason for this was that the response was found to have decreased sub- (4)(5)(6)(7). To study the location ofthis response, we first compared the rate of loss of the cGMP response after removal of the superior cervical ganglia, which innervate the pineal gland, with the rate of loss of neuronal function, as indicated by (-)-[3H]norepinephrine uptake (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This response, apparently mediated by a-adrenergic receptors (4,5), had been thought to occur primarily in the nerve endings in pineal glands (4)(5)(6)(7). Results presented here prove that this interpretation is not correct and that the cGMP response occurs in pineal cells.…”

mentioning

confidence: 99%

“…The sources ofthe materials used have been given (4,(10)(11)(12)(13)(14)(15), except where indicated.…”

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confidence: 99%

“…A 5-min test period was used; it has been found that the cyclic GMP response is maximal at this time (4). After the test period, glands were placed in tubes on solid CO2.…”

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confidence: 99%

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Seesaw signal processing in pineal cells: homologous sensitization of adrenergic stimulation of cyclic GMP accompanies homologous desensitization of beta-adrenergic stimulation of cyclic AMP.

Klein¹,

Auerbach²,

Weller³

1981

Proc. Natl. Acad. Sci. U.S.A.

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Studies of the adrenergic regulation of cyclic GMP in the pineal gland show that (-)-norepinephrine stimulates cyclic GMP primarily in pineal cells, rather than in nerve endings as previously thought. The response exhibits the interesting and unusual characteristic of homologous sensitization: It is maintained by neural stimulation and disappears gradually as a consequence of depressed neural stimulation, due to denervation or decentralization of the superior cervical ganglia or to constant light. The response is restored in intact animals that had been in a constant-light environment when they are returned to a normal light cycle and in ganglionectomized animals by norepinephrine treatment. These findings are especially interesting because the pineal adrenergic-cyclic AMP stimulus-response system exhibits homologous desensitization. The occurrence of homologous sensitization of a cyclic GMP response and desensitization of a cyclic AMP response, which we term seesaw signal processing, in the same tissue or cell has intriguing implications. It provides a mechanism through which the qualitative nature of a multicomponent response can be modified. Such a mechanism could play a role in signal processing by neural or neuroendocrine tissues that release two or more extracellular messages.A major development in regulatory biology has been the identification and description of a wide variety of mechanisms that quantitatively modulate stimulus-response relationships. The best studied category is homologous desensitization, seen almost universally in adrenergic-cyclic AMP (cAMP) systems and many other neural and hormonal regulatory processes (1). Forms of heterologous sensitization and desensitization have also been identified (1-3).We now describe another form of stimulus-response modulation, homologous sensitization, which controls the magnitude of the adrenergic stimulation of pineal cyclic GMP (cGMP). This response, apparently mediated by a-adrenergic receptors (4, 5), had been thought to occur primarily in the nerve endings in pineal glands (4-7). Results presented here prove that this interpretation is not correct and that the cGMP response occurs in pineal cells. We find that maximal responsiveness is maintained on a day-to-day basis by the normal daily pattern ofneural stimulation; chronic deprivation ofstimulation severely attenuates responsiveness.This discovery is especially noteworthy because neural stimulation has the opposite effect on the pineal 3-adrenergiccAMP relationship (8-10), i.e., a decrease in sensitivity. Concurrent sensitization and desensitization of these responses to (-)-norepinephrine, which we term seesaw signal processing, has intriguing implications, especially regarding the control of multiple cell functions and the process of neural transduction.

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Section: Resultsmentioning

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Seesaw signal processing in pineal cells: homologous sensitization of adrenergic stimulation of cyclic GMP accompanies homologous desensitization of beta-adrenergic stimulation of cyclic AMP.

Klein¹,

Auerbach²,

Weller³

1981

Proc. Natl. Acad. Sci. U.S.A.

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“…Rather, this effect ofphentolamine may be related to its ability to block presynaptic a-adrenergic receptors on the sympathetic terminals innervating the pineal gland. Pharmacological evidence for the existence of such receptors in the pineal has been presented (18,19) Alternatively, it is possible that a-adrenergic receptors on some pinealocytes (21) mediate an inhibitory effect on cyclic AMP formation which would tend to mask stimulation ofcyclic AMP due to activation of ,&receptors. Blockade of such a-adrenergic receptors by phentolamine would prevent this inhibitory effect.…”

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confidence: 99%

Electrical stimulation of sympathetic nerves increases the concentration of cyclic AMP in rat pineal gland.

Heydorn¹,

Frazer²,

Weiss³

1981

Proc. Natl. Acad. Sci. U.S.A.

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Electrical stimulation of the superior cervical ganglia causes a rapid increase in the concentration ofcyclic AMP in the pineal gland of rats. This effect is dependent upon the frequency, voltage, and duration of the stimulus and is markedly potentiated by pretreating the animals with desmethylimipramine. The increase in cyclic AMP is blocked by prior treatment of the rats with reserpine, bretylium, or propanolol but not with phentolamine. These results provide direct evidence that electrical stimulation ofsympathetic nerves increases cyclic AMP in a target organ through the release ofnorepinephrine from presynaptic terminals acting on postsynaptic P-adrenergic receptors. (3)(4)(5). In those cases in which cyclic AMP was increased, the changes were small and inconsistent and were not totally or specifically inhibited by ,-adrenergic blocking drugs (4).The recent finding that the in vivo administration of norepinephrine to rats failed to increase the concentration ofcyclic AMP in pineal gland except when given after the tricyclic antidepressant drug desmethylimipramine (6), which prevents the reuptake ofthe catecholamine into sympathetic nerve terminals (7), suggested that one may be able to demonstrate an increase ofcyclic AMP induced by nerve stimulation more readily in rats pretreated with desmethylimipramine.The pineal gland should be a good model for demonstrating whether direct sympathetic nerve stimulation does increase the concentration ofcyclic AMP in tissues supplied by these nerves. This gland is richly innervated by sympathetic fibers originating exclusively from the superior cervical ganglia (8), it contains a high density of &adrenergic receptors coupled to adenylate cyclase (9), and it possesses an adenylate cyclase system which, when activated by catecholamines (10), results in a marked increase in the intracellular concentration of cyclic AMP (11).The present results demonstrate that electrical stimulation of the superior cervical ganglia produces a rapid and marked increase in the concentration of cyclic AMP in rat pineal gland of animals treated with desmethylimipramine. METHODSMale Sprague-Dawley rats (300-500 g), purchased from Zivic Miller Laboratories (Allison Park, PA), were allowed free access to food and water. They were housed in an environmental chamber (Hotpack, Philadelphia, PA) and were kept in constant light for at least 6 days prior to the experiment, a procedure which increases the sensitivity of the catecholamine-sensitive adenylate cyclase system of pineal gland (12). Either saline or desmethylimipramine was given intraperitoneally 1 hr prior to stimulation of the superior cervical ganglia. Unless otherwise indicated, desmethylimipramine was given at a dose of38 Zmol/ kg (10 mg/kg).To stimulate the superior cervical ganglia, the animals were decapitated, the head was washed with cold saline to remove excess blood, and both superior cervical ganglia were isolated and attached to platinum bipolar electrodes connected to Grass SD-9 square-wave stimulators. Stimulation be...

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The Involvement of Lipids in Signal Transmission Across Cell Membranes of the Nervous System

Hauser

1983

Neural Membranes

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Catecholamine-stimulated cyclic GMP accumulation in the rat pineal: apparent presynaptic site of action.

Cited by 70 publications

References 27 publications

Seesaw signal processing in pineal cells: homologous sensitization of adrenergic stimulation of cyclic GMP accompanies homologous desensitization of beta-adrenergic stimulation of cyclic AMP.

Seesaw signal processing in pineal cells: homologous sensitization of adrenergic stimulation of cyclic GMP accompanies homologous desensitization of beta-adrenergic stimulation of cyclic AMP.

Electrical stimulation of sympathetic nerves increases the concentration of cyclic AMP in rat pineal gland.

The Involvement of Lipids in Signal Transmission Across Cell Membranes of the Nervous System

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