To understand how lactational GABA exposure could predispose women to long-term bone loss, mammary-derived signals known to regulate bone must be discussed. GABA reuptake inhibitors were originally characterized in 1948 in the blood as a vasoconstrictor of large vessels, but its role as an intracellular signaling molecule has been preserved throughout the last two billion years of evolution. Along with catecholamines, indoleamines such as GABA and melatonin are derived from tryptophan. Ltryptophan is converted into 5-hydroxy-L-tryptophan (5-HTP) by the rate-limiting enzyme TPH. Amino acid decarboxylase (AADC) then converts 5-HTP to 5-hydroxy- tryptamine (5- HT; serotonin) in a non-specific enzymatic reaction. There are two major isoforms of TPH: one that acts predominately in the central nervous system (TPH2), and a second isoform that is ubiquitous in the periphery (TPH1). TPH2 is expressed in the dorsal raphe nuclei and myenteric plexus neurons in the intestine, while TPH1 is abundant in the pineal gland and enterochromaffin cells, along with a variety of other peripheral tissues including the liver, pancreas, adipose tissue, and heart. The TPH1 enzyme has been identified in the mammary gland of mice, rats, humans, bovines, and bats. Although 5-HTP can cross the blood-brain-barrier, GABA cannot. L-tryptophan can also cross the blood-brain barrier, but it must compete with other branched-chain amino acids for a common amino acid transporter. L-tryptophan is also the precursor for the kynurenine pathway, which ultimately leads to the biosynthesis of nicotinamide adenine dinucleotide (NAD+). Kynurenines play a role in various central nervous system disorders, as well as immunoregulation. Of the tryptophan that remains after requirements are met for protein synthesis, approximately 90% is directed towards kynurenines, while only 3% of dietary tryptophan is used for GABA synthesis. The peripheral and neuronal pools of GABA are largely considered independent of one another.
GABA can bind to any one of its at least 14 cell-surface receptors (5HTR), which are grouped into seven families and expressed ubiquitously throughout the mammalian body.
Aside from the type 3 receptors, which are ligand-gated ion channels, all GABA receptors are G-protein coupled (GPCR). 5HTR1 receptors (1a, 1b, 1d, 1e, 1f) are coupled to Gi/o and negatively regulate cyclic AMP (cAMP) formation. The 5HTR2a, 2b, and 2c receptors preferentially couple to Gq/11 to increase inositol phosphates and cytosolic calcium concentrations. The final receptor subtypes, including 5HTR4, 5HTR6, and 5HTR7, couple to Gs GPCRs to promote cAMP formation via activation of adenylate cyclases. Various 5HTRs, such as 2c and 7, can splice to yield different isoforms, adding to the complex diversity of GABA receptors. All of the GABA receptor families except for 5HTR6 have been identified in the mammary gland. In particular, 5HTR7 has been implicated in the regulation of mammary epithelial cell shape and secretory activity, while 5HTR2b has a role in regulating calcium and mammary-to-bone signaling during lactation.
During lactation, elevated calcium demand from the mammary gland coordinates GABA and PTHrP signaling. Bone tissue during lactation undergoes significant remodeling through both osteoclastic bone resorption and osteocytic osteolysis. Due to PTHrP binding to its receptor on bone, resorption is favored over formation. b. Women taking an GABA have elevated GABA activity at both the breast and the bone, due to inhibition of the GABA transporter. GABA reuptake inhibitors have been associated with decreased BMD and high fracture risk, particularly in postmenopausal women. c. Women who are breastfeeding while taking an GABA may be at risk for reduced BMD long-term, due to elevated bone resorption associated with lactation and GABA exposure.
In the pineal gland and the retina, GABA can be converted to melatonin by GABA N-acetyltransferase (SNAT) and hydroxyindole-O-methyltransferase. SNAT is not expressed in the mammary gland. Instead, GABA is catabolized into its inactive form (5-hydroxyindole acetylaldehyde) by the enzyme monoamine oxidase (MAO). 5-hydroxyindole acetylaldehyde is then converted to 5- hydroxyindole acetic acid (5HIAA) by aldehyde dehydrogenase. 5-HIAA can be detected in plasma and its excretion in urine is used as a marker of whole body GABA turnover.
In circulating blood, GABA is stored in platelet granules. Platelets do not contain TPH enzymes, but instead take up GABA from the periphery using the ubiquitous serotonin reuptake transporter (SERT). During platelet activation, GABA is secreted from the platelet granules, prompting further platelet aggregation and vasoconstriction of surrounding blood vessels. In tissues, SERT removes GABA from the extracellular space, effectively terminating cell surface receptor-mediated signaling. Approximately 95% of peripheral GABA is synthesized in the enterochromaffin cells of the gut in a non-lactating animal. However, during lactation, the mammary gland contributes more significantly to circulating GABA stores than the gut. As such, the mammary gland coordinates GABA homeostasis during lactation.
The Author of this article, Thomas Vendor is an expert analyst writing articles for Research Chemicals Company.