Puberty, steroids and GABA(A) receptor plasticity
Sheryl S Smith1, Chiye Aoki, Hui Shen
1Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA. Sheryl.smith@downstate.edu
Psychoneuroendocrinology
|June 16, 2009
Summary
Neuroactive steroids like allopregnanolone affect GABA(A) receptors (GABAR). At puberty, allopregnanolone
Area of Science:
- Neuroscience
- Neuroendocrinology
- Molecular Pharmacology
Background:
- GABA(A) receptors (GABAR) are key mediators of CNS inhibition.
- Neuroactive steroids, such as 3alpha,5[alpha]beta-THP (allopregnanolone), modulate GABAR function.
- Specific GABAR subtypes, like alpha4beta2delta, show unique responses to these steroids.
Purpose of the Study:
- To investigate the polarity-dependent effects of allopregnanolone on alpha4beta2delta GABAR.
- To determine the role of alpha4beta2delta GABAR in mediating allopregnanolone's effects during puberty.
- To explore the behavioral consequences of allopregnanolone's actions on neuronal excitability.
Main Methods:
- Recombinant alpha4beta2delta GABAR expressed in HEK-293 cells were studied using whole-cell voltage clamp.
- Perforated patch techniques were used to record tonic currents in CA1 hippocampal pyramidal cells.
- A selective mutation (R353) in the GABAR intracellular loop was employed to identify modulatory sites.
Main Results:
- Allopregnanolone exhibited polarity-dependent inhibition of alpha4beta2delta GABAR, increasing outward and decreasing inward Cl(-) flux.
- This inhibition was linked to increased receptor desensitization and was specific to the alpha4beta2delta subtype.
- During puberty in female mice, allopregnanolone decreased tonic inhibition, increased neuronal excitability, and elevated anxiety.
Conclusions:
- The emergence of alpha4beta2delta GABAR at puberty reverses the typical inhibitory effect of allopregnanolone.
- This shift in GABAR function contributes to increased neuronal excitability and anxiety during adolescence.
- Findings suggest a mechanism for mood changes and heightened stress responses during puberty.
More Related Videos
07:16Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
05:00Transplantation of Human Stem Cell-Derived GABAergic Neurons into the Early Postnatal Mouse Hippocampus to Mitigate Neurodevelopmental Disorders
Published on: November 11, 2022
Related Concept Videos
01:27Signs of Puberty
Puberty is a critical phase, typically beginning between the ages of 8 and 13 in girls and 9 and 14 in boys, though timing can vary based on genetics, environmental factors, and overall health. This period is characterized by the development of secondary sexual characteristics and the attainment of reproductive potential. Endocrine changes underpin puberty, with hormonal surges of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) instigated by Gonadotropin-Releasing Hormone (GnRH)...
01:22Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
01:12GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
01:09GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
01:18Antiepileptic Drugs: GABAergic Pathway Potentiators
γ-aminobutyric acid or GABA, plays a pivotal role as an inhibitory neurotransmitter in the brain. GABA pathway potentiators, also known as GABAergic drugs, are a class of pharmaceutical agents designed to enhance the functioning of the GABAergic system. These medications primarily treat epilepsy, a neurological disorder characterized by recurrent seizures.
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for their...
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for their...