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Modulation of Adrenergic Receptors During Aging
Neurobiology of Aging, Vol. 9, pp. 61-62. © Pergamon Journals Ltd., 1988. Printed in the U.S.A.
0197-4580/88 $3.00.4- .00
Modulation of Adrenergic Receptors During Aging BENJAMIN
WEISS
Division of Neuropsychopharmacology, Department of Pharmacology Medical College of Pennsylvania at Eastern Pennsylvania Psychiatric Institute Philadelphia, Pit
In aging there is not only a reduced density of adrenergic receptors but also a reduced capacity to adapt these receptors to a changing neuronal input or hormonal environment. A reduced density of receptors presumably would result in a decreased ability of aged individuals to respond to stimulation of these receptors, and a reduced ability to modulate these receptors would result in a decreased capacity to adapt their responses to a changing internal or external environment. Future studies should be directed at the genomic mechanisms that control receptor synthesis. T H E review by Scarpace and Abrass entitled "Alpha- and Beta-Adrenergic Receptor Function" provides a useful summary of an extremely important area of aging research. The issues raised are not only academically interesting but also have practical implications. That is, the question of how responses mediated by neuronal or hormonal events can be regulated and modulated, and how this process may be altered in advanced age are of paramount importance in understanding how an aged organism functions. It is obvious that an organism must be able to perform two opposing types of modulation related to its response to stimuli. On the one hand, it must be able to maintain a degree of homeostasis and resist changes in its responses in the face of a constantly changing environment. On the other hand, under certain circumstances, it must be capable of rapidly and profoundly changing the degree to which it responds to neuronal or hormonal stimuli. The latter situation could be effected with positive feedback systems whereby one of the products of the reaction can feed back to cause a further change in the same direction as that of the initial change. An example of a positive feedback system involving receptor modulation is the inter-relationship that exists between the pineal gland and the ovary [13]. The pineal gland, once activated by catecholamines, synthesizes melatonin. Melatonin is antigonadotropic and causes a decreased release of estrogen from the ovary. Estrogen, in turn, decreases the density of beta adrenergic receptors in the pineal gland [13]. As a result of this interaction, a decreased release of estrogen initiates a mechanism in the pineal gland that causes a further decrease in the release of estrogen. The opposite will also occur; an increase in estrogen, by inhibiting beta receptors in the pineal gland decreases the synthesis of melatonin, res~ting in a further increase in estrogen. This positive feedback system thereby provides abrupt and marked changes in the synthesis and release of estrogen, a situation which is essential for the proper functioning of the ovary. Maintaining homeostasis is often accomplished with the use of negative feedback mechanisms. Once activated, the system can feed back to cause a decreased responsiveness to subsequent stimulation of this system. This negative feedback may occur rapidly (within seconds) or may take place over hours, days or even years.
Using an example of receptor mediated events, rapid decreases in responses may be caused by an uncoupling of the receptor from the second messenger enzyme system or by an invagination of the receptor into the cell so that it is no longer accessible to the agonist [7]. Long term changes in responses may occur by a related but somewhat different mechanism. This may involve alterations in the number or density of receptors, resulting from either an increased metabolism or decreased synthesis of receptors [4]. An increased destruction of receptors may result from a persistent activation of receptors leading to an invagin~tion and subsequent metabolic breakdown of the receptors by intracellular lysosomal enzymes [3,10]. Decreased synthesis of receptors may result from changes in the genetic or protein synthetic machinery itself. This decreased density of receptors, regardless of its cause, is usually referred to as receptor down-regulation. The converse of this is that decreased neural or hormonal input to a system can cause an increase or up-regulation of postsynaptic receptor systems. This has been abundantly demonstrated in catecholaminergic systems, particularly with the beta adrenergic receptor-linked ~denylate cyclase complex [ 12]. This process is essential for allowing an organism to adapt to changes in its environment and to compensate for any decreases in neuronal or hormonal input such as that which may occur during aging. It is this adaptive mechanism that appears to be deficient in advanced age. During the aging process, there may be a persistent decrease in neuronal input caused, for example, by neuronal degeneration, or there may be a decrease in hormonal input caused by decreased function of endocrine glands. Ordinarily the young organism can compensate for the decreased neuronal or hormonal input by adapting the density of its post synaptic receptors [ 1, 11, 15]. In advanced age the mechanisms by which certain receptors are regulated appear to be deficient, resulting in an age-related decreased ability to compensate to changes in the neuronal or hormonal environment [5,14]. This inability to compensate may be explained by the experimental data showing that adrenergic receptors are not synthesized as rapidly in old animals as they are in young ones [6,17]. The specific site and mechanism which is responsible for this defect is still unclear but could be either at the transcriptional, transla-
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tional or even post-translational stage of receptor synthesis. Of course not all age-related decreases in function are attributable to alterations in post synaptic receptors. Many other sites and mechanisms may be involved, including defects in presynaptic events or in postsynaptic sites that are beyond the receptors, such as coupling mechanisms, protein kinases, phospholipases, and other intraceHular sites [8,9]. Indeed, in some cases investigators have failed to find a decreased density of receptors even though there is a decreased function in the tissue being examined. Although there may, in fact, be no age-related change in receptors, the inability to demonstrate any alterations in receptors may be explained by the technique used to measure the receptors. For example, an invagination of surface receptors may make them inaccessible to activation by an agonist but they would still appear to be present when they are assayed in broken cell preparations.
Another issue that should be stressed is that all changes associated with aging do not occur at the same time in the life cycle of an organism. The mechanisms which control different types of receptors or which control the same receptors in different tissues may change at different rates and at different ages [2,16]. In a broader sense aging should be viewed as a continuum, which encompasses changes that take place during ontogeny as well as those that take place during maturation and advanced age. Whatever the mechanisms involved, clearly there are age-related changes that profoundly affect the function of an organism and its ability to adapt to its environment. Where this age-related defect lies and how this can be overcome is the challenge for the future. The directions, however, are clear. One must learn more about the factors that control the synthesis of receptors at the molecular and genomic levels.
REFERENCES 1. Cantor, E. H., L. H. Greenberg and B. Weiss. Effect of long term changes in sympathetic nervous activity on the betaadrenergic receptor adenylate cyclase complex of rat pineal gland. Mol Pharmacol 19: 21-26, 1981. 2. Cantor, E., M. B. Clark and B. Weiss. Effect of sympathetic input on ontogeny of beta-adrenergic receptors in rat pineal gland. Brain Res Bull 7: 243-247, 1981. 3. Chuang, D. M. and E. Costa. Evidence for internalization of the recognition site of beta-adrenergic receptors during receptor subsensitivity induced by (-) isoproterenol. Proc Natl Acad USA 76: 3024-3028, 1979. 4. Doss, R. C., J. P. Perkins and T. K. Harden. Recovery of betaadrenergic receptors following long term exposure of astrocytoma cells to catecholamines: role of protein synthesis. J Biol Chem 256: 12281-12286, 1981. 5. Freilich, J. and B. Weiss. Altered adaptive capacity of brain catecholaminergic receptors during aging. In: The Aging o f the Brain, edited by D. Samuel, S. Algeri, S. Gershon, V. E. Grimm and G. Toffano. New York: Raven Press, 1983, pp. 277-300. 6. Greenberg, L. H., D. J. Brunswick and B. Weiss. Effect of age on the rate of recovery of beta-adrenergic receptors in rat brain following desmethylimipramine-induced subsensitivity. Brain Res 328: 81-88, 1985. 7. Harden, T. K. Agonist-induced desensitization of the betaadrenergic receptor-linked adenylate cyclase. Pharmacol Rev 35: 5-32, 1983. 8. Lefkowitz, R. J., J. M. Stadel and M. G. Caron. Adenylate cyclase-coupled beta-adrenergic receptors: structure and mechanisms of activation and desensitization. Annu Rev Biochem 52: 159-186, 1983. 9. Roberts-Lewis, J. M., P. H. Roseboom, L. M. Iwaniec and M. E. Gnegy. Differential down-regulation of D rstimulated adenylate cyclase activity in rat forebraln after in vivo amphetamine treatments. J Neurosci 6: 2245-2251, 1986.
10. Sibley, D. R. and R. J. Lefkowitz. Molecular mechanisms of receptor densensitization using the beta-adrenergic receptorcoupled adenylate cyclase system as a model. Nature 317: 124129, 1985. I I. Weiss, B. Effects of environmental lighting and chronic denerration on the activation of adenyl cyclase of rat pineal gland by norepinephrine and sodium fluoride. J Pharmacol Exp Ther 168: 146--152, 1969. 12. Weiss, B., L. H. Greenberg and M. B. Clark. Physiological and pharmacological modulation of the beta-adrenergic receptorlinked adenylate cyclase system: supersensitivity and subsensitivity. In: Dynamics o f Neurotransmitter Function, edited by I. Hanin. New York: Raven Press, 1984, pp. 319-330. 13. Weiss, B. and S. J. Strada. Neuroendocrine control of the cyclic AMP system of brain and pineal gland. Adv Cyclic Nucleotide Res 1: 357-374, 1972. 14. Weiss, B., L. H. Greenberg and E. Cantor. Age-related alterations in the development of adrenergic denervation supersensitivity. Fed Proc 38: 1915-1921, 1979. 15. Weiss, B. and J. Crayton. Neural and hormonal regulation of pineal adenyl cyclase activity. In: Role o f Cyclic A M P in Cell Function: Advances in Biochemical Psychopharmacology, Vol 3, edited by E. Costa and P. Greengard. New York: Raven Press, 1970, pp. 217-239. 16. Weiss, B., M. B. Clark and L. H. Greenberg. Modulation of catecholaminergic receptors during development and aging. In: Handbook ofNeurochemistry, Vol 6, edited by A. Lajtha. New York: Plenum Press, 1984, pp. 595-627. 17. Zhou, L. W., B. Weiss, J. S. Freilich and L. H. Greenberg. Impaired recovery of alpha~ and alpha2-adrenergic receptors in brain tissue of aged rats. J Gerontol 39: 538-546, 1984.
0197-4580/88 $3.00.4- .00
Modulation of Adrenergic Receptors During Aging BENJAMIN
WEISS
Division of Neuropsychopharmacology, Department of Pharmacology Medical College of Pennsylvania at Eastern Pennsylvania Psychiatric Institute Philadelphia, Pit
In aging there is not only a reduced density of adrenergic receptors but also a reduced capacity to adapt these receptors to a changing neuronal input or hormonal environment. A reduced density of receptors presumably would result in a decreased ability of aged individuals to respond to stimulation of these receptors, and a reduced ability to modulate these receptors would result in a decreased capacity to adapt their responses to a changing internal or external environment. Future studies should be directed at the genomic mechanisms that control receptor synthesis. T H E review by Scarpace and Abrass entitled "Alpha- and Beta-Adrenergic Receptor Function" provides a useful summary of an extremely important area of aging research. The issues raised are not only academically interesting but also have practical implications. That is, the question of how responses mediated by neuronal or hormonal events can be regulated and modulated, and how this process may be altered in advanced age are of paramount importance in understanding how an aged organism functions. It is obvious that an organism must be able to perform two opposing types of modulation related to its response to stimuli. On the one hand, it must be able to maintain a degree of homeostasis and resist changes in its responses in the face of a constantly changing environment. On the other hand, under certain circumstances, it must be capable of rapidly and profoundly changing the degree to which it responds to neuronal or hormonal stimuli. The latter situation could be effected with positive feedback systems whereby one of the products of the reaction can feed back to cause a further change in the same direction as that of the initial change. An example of a positive feedback system involving receptor modulation is the inter-relationship that exists between the pineal gland and the ovary [13]. The pineal gland, once activated by catecholamines, synthesizes melatonin. Melatonin is antigonadotropic and causes a decreased release of estrogen from the ovary. Estrogen, in turn, decreases the density of beta adrenergic receptors in the pineal gland [13]. As a result of this interaction, a decreased release of estrogen initiates a mechanism in the pineal gland that causes a further decrease in the release of estrogen. The opposite will also occur; an increase in estrogen, by inhibiting beta receptors in the pineal gland decreases the synthesis of melatonin, res~ting in a further increase in estrogen. This positive feedback system thereby provides abrupt and marked changes in the synthesis and release of estrogen, a situation which is essential for the proper functioning of the ovary. Maintaining homeostasis is often accomplished with the use of negative feedback mechanisms. Once activated, the system can feed back to cause a decreased responsiveness to subsequent stimulation of this system. This negative feedback may occur rapidly (within seconds) or may take place over hours, days or even years.
Using an example of receptor mediated events, rapid decreases in responses may be caused by an uncoupling of the receptor from the second messenger enzyme system or by an invagination of the receptor into the cell so that it is no longer accessible to the agonist [7]. Long term changes in responses may occur by a related but somewhat different mechanism. This may involve alterations in the number or density of receptors, resulting from either an increased metabolism or decreased synthesis of receptors [4]. An increased destruction of receptors may result from a persistent activation of receptors leading to an invagin~tion and subsequent metabolic breakdown of the receptors by intracellular lysosomal enzymes [3,10]. Decreased synthesis of receptors may result from changes in the genetic or protein synthetic machinery itself. This decreased density of receptors, regardless of its cause, is usually referred to as receptor down-regulation. The converse of this is that decreased neural or hormonal input to a system can cause an increase or up-regulation of postsynaptic receptor systems. This has been abundantly demonstrated in catecholaminergic systems, particularly with the beta adrenergic receptor-linked ~denylate cyclase complex [ 12]. This process is essential for allowing an organism to adapt to changes in its environment and to compensate for any decreases in neuronal or hormonal input such as that which may occur during aging. It is this adaptive mechanism that appears to be deficient in advanced age. During the aging process, there may be a persistent decrease in neuronal input caused, for example, by neuronal degeneration, or there may be a decrease in hormonal input caused by decreased function of endocrine glands. Ordinarily the young organism can compensate for the decreased neuronal or hormonal input by adapting the density of its post synaptic receptors [ 1, 11, 15]. In advanced age the mechanisms by which certain receptors are regulated appear to be deficient, resulting in an age-related decreased ability to compensate to changes in the neuronal or hormonal environment [5,14]. This inability to compensate may be explained by the experimental data showing that adrenergic receptors are not synthesized as rapidly in old animals as they are in young ones [6,17]. The specific site and mechanism which is responsible for this defect is still unclear but could be either at the transcriptional, transla-
61
62
WEISS
tional or even post-translational stage of receptor synthesis. Of course not all age-related decreases in function are attributable to alterations in post synaptic receptors. Many other sites and mechanisms may be involved, including defects in presynaptic events or in postsynaptic sites that are beyond the receptors, such as coupling mechanisms, protein kinases, phospholipases, and other intraceHular sites [8,9]. Indeed, in some cases investigators have failed to find a decreased density of receptors even though there is a decreased function in the tissue being examined. Although there may, in fact, be no age-related change in receptors, the inability to demonstrate any alterations in receptors may be explained by the technique used to measure the receptors. For example, an invagination of surface receptors may make them inaccessible to activation by an agonist but they would still appear to be present when they are assayed in broken cell preparations.
Another issue that should be stressed is that all changes associated with aging do not occur at the same time in the life cycle of an organism. The mechanisms which control different types of receptors or which control the same receptors in different tissues may change at different rates and at different ages [2,16]. In a broader sense aging should be viewed as a continuum, which encompasses changes that take place during ontogeny as well as those that take place during maturation and advanced age. Whatever the mechanisms involved, clearly there are age-related changes that profoundly affect the function of an organism and its ability to adapt to its environment. Where this age-related defect lies and how this can be overcome is the challenge for the future. The directions, however, are clear. One must learn more about the factors that control the synthesis of receptors at the molecular and genomic levels.
REFERENCES 1. Cantor, E. H., L. H. Greenberg and B. Weiss. Effect of long term changes in sympathetic nervous activity on the betaadrenergic receptor adenylate cyclase complex of rat pineal gland. Mol Pharmacol 19: 21-26, 1981. 2. Cantor, E., M. B. Clark and B. Weiss. Effect of sympathetic input on ontogeny of beta-adrenergic receptors in rat pineal gland. Brain Res Bull 7: 243-247, 1981. 3. Chuang, D. M. and E. Costa. Evidence for internalization of the recognition site of beta-adrenergic receptors during receptor subsensitivity induced by (-) isoproterenol. Proc Natl Acad USA 76: 3024-3028, 1979. 4. Doss, R. C., J. P. Perkins and T. K. Harden. Recovery of betaadrenergic receptors following long term exposure of astrocytoma cells to catecholamines: role of protein synthesis. J Biol Chem 256: 12281-12286, 1981. 5. Freilich, J. and B. Weiss. Altered adaptive capacity of brain catecholaminergic receptors during aging. In: The Aging o f the Brain, edited by D. Samuel, S. Algeri, S. Gershon, V. E. Grimm and G. Toffano. New York: Raven Press, 1983, pp. 277-300. 6. Greenberg, L. H., D. J. Brunswick and B. Weiss. Effect of age on the rate of recovery of beta-adrenergic receptors in rat brain following desmethylimipramine-induced subsensitivity. Brain Res 328: 81-88, 1985. 7. Harden, T. K. Agonist-induced desensitization of the betaadrenergic receptor-linked adenylate cyclase. Pharmacol Rev 35: 5-32, 1983. 8. Lefkowitz, R. J., J. M. Stadel and M. G. Caron. Adenylate cyclase-coupled beta-adrenergic receptors: structure and mechanisms of activation and desensitization. Annu Rev Biochem 52: 159-186, 1983. 9. Roberts-Lewis, J. M., P. H. Roseboom, L. M. Iwaniec and M. E. Gnegy. Differential down-regulation of D rstimulated adenylate cyclase activity in rat forebraln after in vivo amphetamine treatments. J Neurosci 6: 2245-2251, 1986.
10. Sibley, D. R. and R. J. Lefkowitz. Molecular mechanisms of receptor densensitization using the beta-adrenergic receptorcoupled adenylate cyclase system as a model. Nature 317: 124129, 1985. I I. Weiss, B. Effects of environmental lighting and chronic denerration on the activation of adenyl cyclase of rat pineal gland by norepinephrine and sodium fluoride. J Pharmacol Exp Ther 168: 146--152, 1969. 12. Weiss, B., L. H. Greenberg and M. B. Clark. Physiological and pharmacological modulation of the beta-adrenergic receptorlinked adenylate cyclase system: supersensitivity and subsensitivity. In: Dynamics o f Neurotransmitter Function, edited by I. Hanin. New York: Raven Press, 1984, pp. 319-330. 13. Weiss, B. and S. J. Strada. Neuroendocrine control of the cyclic AMP system of brain and pineal gland. Adv Cyclic Nucleotide Res 1: 357-374, 1972. 14. Weiss, B., L. H. Greenberg and E. Cantor. Age-related alterations in the development of adrenergic denervation supersensitivity. Fed Proc 38: 1915-1921, 1979. 15. Weiss, B. and J. Crayton. Neural and hormonal regulation of pineal adenyl cyclase activity. In: Role o f Cyclic A M P in Cell Function: Advances in Biochemical Psychopharmacology, Vol 3, edited by E. Costa and P. Greengard. New York: Raven Press, 1970, pp. 217-239. 16. Weiss, B., M. B. Clark and L. H. Greenberg. Modulation of catecholaminergic receptors during development and aging. In: Handbook ofNeurochemistry, Vol 6, edited by A. Lajtha. New York: Plenum Press, 1984, pp. 595-627. 17. Zhou, L. W., B. Weiss, J. S. Freilich and L. H. Greenberg. Impaired recovery of alpha~ and alpha2-adrenergic receptors in brain tissue of aged rats. J Gerontol 39: 538-546, 1984.