Molecular components and mechanism of adrenergic signal transduction in mammalian pineal gland: regulation of melatonin synthesis.

Mar 24, 2005Indian journal of experimental biology

Key molecules and process behind adrenaline signals controlling melatonin production in the mammal pineal gland

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Abstract

Increased secretion of norepinephrine (NE) during the first half of the night stimulates melatonin synthesis by several folds.

Rhythmic neural outputs from the hypothalamic suprachiasmatic nucleus regulate the release of NE, influencing melatonin production.
NE binds to specific receptors on pinealocytes, initiating signal transduction through cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) pathways.
This signal transduction enhances the expression and activity of the enzyme N-acetyltransferase, crucial for melatonin synthesis during early night hours.
Simultaneously, the expression of inducible cAMP early repressor (ICER) negatively regulates melatonin synthesis, affecting the rhythm's amplitude.
In the second half of the night, increased acetylcholine release and reduced NE secretion lead to the cessation of melatonin synthesis.

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Rhythmic neural outputs from the hypothalamic suprachiasmatic nucleus (SCN), which programme the rhythmic release of norepinephrine (NE) from intrapineal nerve fibers, regulate circadian rhythm of melatonin synthesis. Increased secretion of NE with the onset of darkness during the first half of night stimulates melatonin synthesis by several folds. NE binds to both alpha1- and beta-adrenergic receptors present on the pinealocyte membrane and initiates adrenergic signal transduction via cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) generating pathways. The NE-induced adrenergic signal transduction switches 'on' melatonin synthesis during the early hours of night by stimulating expression of the rate-limiting enzyme of melatonin synthesis, N-acetyltransferase (AA-NAT) via cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-cAMP response element (CRE) pathway as well as by increasing AA-NAT activity via cAMP-PKA-14-3-3 protein pathway. Simultaneously, adrenergically-induced expression of inducible cAMP early repressor (ICER) negatively regulates aa-nat gene expression and controls the amplitude of melatonin rhythm. In the second half of night, increased release of acetylcholine from central pinealopetal projections, inhibition of NE secretion by SCN, withdrawal of adrenergic inputs and reversal of events that took place in the first half lead to switching 'off' of melatonin synthesis. Adrenergic signal transduction via cGMP-protein kinase G (PKG)-mitogen activated protein kinase (MAPK)-ribosomal S6 kinase (RSK) pathway also seems to be fully functional, but its role in modulation of melatonin synthesis remains unexplored. This article gives a critical review of information available on various components of the adrenergic signal transduction cascades involved in the regulation of melatonin synthesis.

Molecular components and mechanism of adrenergic signal transduction in mammalian pineal gland: regulation of melatonin synthesis.

Abstract

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