TY - JOUR
T1 - Ontogeny and regulation of the serotonin transporter
T2 - Providing insights into human disorders
AU - Daws, Lynette C.
AU - Gould, Georgianna G.
N1 - Funding Information:
Supported in part from USPHS grant MH64489 (LCD), MH064489-07S1 , (LCD), NARSAD (LCD) and the San Antonio Area Foundation (GGG).
PY - 2011/7
Y1 - 2011/7
N2 - Serotonin (5-hydroxytryptamine, 5-HT) was one of the first neurotransmitters for which a role in development was identified. Pharmacological and gene knockout studies have revealed a critical role for 5-HT in numerous processes, including cell division, neuronal migration, differentiation and synaptogenesis. An excess in brain 5-HT appears to be mechanistically linked to abnormal brain development, which in turn is associated with neurological disorders. Ambient levels of 5-HT are controlled by a vast orchestra of proteins, including a multiplicity of pre- and post-synaptic 5-HT receptors, heteroreceptors, enzymes and transporters. The 5-HT transporter (SERT, 5-HTT) is arguably the most powerful regulator of ambient extracellular 5-HT. SERT is the high-affinity uptake mechanism for 5-HT and exerts tight control over the strength and duration of serotonergic neurotransmission. Perturbation of its expression level or function has been implicated in many diseases, prominent among them are psychiatric disorders. This review synthesizes existing information on the ontogeny of SERT during embryonic and early postnatal development though adolescence, along with factors that influence its expression and function during these critical developmental windows. We integrate this knowledge to emphasize how inappropriate SERT expression or its dysregulation may be linked to the pathophysiology of psychiatric, cardiovascular and gastrointestinal diseases.
AB - Serotonin (5-hydroxytryptamine, 5-HT) was one of the first neurotransmitters for which a role in development was identified. Pharmacological and gene knockout studies have revealed a critical role for 5-HT in numerous processes, including cell division, neuronal migration, differentiation and synaptogenesis. An excess in brain 5-HT appears to be mechanistically linked to abnormal brain development, which in turn is associated with neurological disorders. Ambient levels of 5-HT are controlled by a vast orchestra of proteins, including a multiplicity of pre- and post-synaptic 5-HT receptors, heteroreceptors, enzymes and transporters. The 5-HT transporter (SERT, 5-HTT) is arguably the most powerful regulator of ambient extracellular 5-HT. SERT is the high-affinity uptake mechanism for 5-HT and exerts tight control over the strength and duration of serotonergic neurotransmission. Perturbation of its expression level or function has been implicated in many diseases, prominent among them are psychiatric disorders. This review synthesizes existing information on the ontogeny of SERT during embryonic and early postnatal development though adolescence, along with factors that influence its expression and function during these critical developmental windows. We integrate this knowledge to emphasize how inappropriate SERT expression or its dysregulation may be linked to the pathophysiology of psychiatric, cardiovascular and gastrointestinal diseases.
KW - Antidepressants
KW - Cardiovascular and gastrointestinal disease
KW - Gene variants
KW - Ontogeny
KW - Psychiatric disease
KW - Serotonin transporter
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U2 - 10.1016/j.pharmthera.2011.03.013
DO - 10.1016/j.pharmthera.2011.03.013
M3 - Review article
C2 - 21447358
AN - SCOPUS:79956198390
SN - 0163-7258
VL - 131
SP - 61
EP - 79
JO - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and
JF - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and
IS - 1
ER -