Glycine Transporters and Hereditary Hyperekplexia Quiz

GABA & Glycine

• GABA and glycine are neurotransmitters, crucial for inhibitory functions in the adult nervous system.
• Ironically, the precursor to GABA is glutamate, a major excitatory neurotransmitter.
• GABA is synthesized via the enzyme glutamic acid decarboxylase (GAD).
• GAD (65 and/or 67) is localized specifically on GABAergic neurons.
• GABA is present throughout the brain in diverse inhibitory interneurons (e.g., basket, stellate) and projection neurons (e.g., Purkinje).
• GABA is transported back into GABAergic terminals via dedicated GABA transporters.
• GABA is also buffered by astrocytes where it is degraded by GABA transaminase (GABA-T).
• This process results in a net flow of GABA from neuronal to astrocytic compartments.
• Compensatory flow of a GABA precursor is needed to maintain this balance.
• GABA-related proteins like GAD, GABA-T, and GATs have specific locations and functions.
• GABA receptors (GABAA, GABAB, GABAC) have diverse roles and are modulated by various substances (e.g., alcohol, anaesthetics, benzodiazepines, etc).

Receptor Nomenclature

• GABA receptors form complexes with different subunits (homomeric and heteromeric), and their respective types.
• GABA_A, GABA_B, and GABA_C receptors have differing properties including the types of ions involved, their locations, and their roles in the nervous system.
• The Greek letters denote subunit families, each with significant homology in amino acid sequence (specifically about 70%).
• The related homology between families is around 30-40%.
• GABAA receptors are chloride channels, while GABAB is a G protein-coupled receptor.
• GABA_C receptors are homomeric, containing only rho subunits.

Drugs Affecting GABAergic Transmission

• Drugs can modulate GABAergic transmission through various mechanisms.
• Agonists often enhance GABAergic activity, and antagonists reduce it.
• Different drugs target different GABA receptors.
• Examples of drugs impacting relevant receptors include benzodiazepines, barbiturates, and some anaesthetics.

Case Study - Adulteration

• The case study involving the adulteration of beer exemplifies the use of various substances to alter flavour and perceived strength, including toxins and other harmful compounds.
• Brewers used different products, such as cocculus indicus in an attempt to enhance flavour and masking of poor products.
• Authorities took measures to control these adulteration practices.

Case Study - Performance Enhancement

• Historically, substances like strychnine were used as performance enhancers.
• Strychnine is a potent convulsant, and its use in sports competitions was a significant concern.
• Athletic performance enhancers have ethical and legal implications.
• Contemporary athletic guidelines address the use of performance-enhancing substances.

Glycine in Synaptic Transmission

• Glycine is a major neurotransmitter in the nervous system, and it has similar characteristics to GABA.
• Glycine is synthesized from serine by serine hydroxymethyltransferase (SMHT).
• Glycine is packaged into vesicles, transported in the synaptic cleft by uptake transporters on astrocytes and presynaptic terminals (GLYT1 and GLYT2).
• GLYT1 and GLYT2 are expressed throughout the brain, performing a crucial role.
• Degradation occurs through the glycine cleavage system in mitochondria. Glycine receptors are impacted by various drugs.

Glycine Receptors

• Glycine receptors are a class of ionotropic receptors, with specific subunit compositions and functions.
• Glycine receptors are related to nicotinic cholinergic and 5-HT3 receptors, possessing a pentameric structure.
• Glycine receptors are activated by glycine and are inhibited by strychnine.
• Glycine receptors have specific regional and developmental regulation, notably with the alpha subunits determining location, influencing the physiological roles of glycine.

Ethanol and GABA/Glycine Receptors

• Ethanol enhances GABA_A receptor-mediated synaptic inhibition.
• Ethanol affects GABA_A receptor function and consequently increases efficacy of glycine.
• Blocking GABA_B receptors enhances effect of ethanol.
• Ethanol may impact other neurotransmitter systems like glutamate in different ways.

GABA and Disease

• GABAergic neurotransmission plays a role in various neuropsychiatric disorders, including epilepsy, Huntington's disease, tardive dyskinesia, alcoholism and sleep disorders.
• In some conditions, imbalances in GABA neurotransmission can affect neuronal activity, contributing to disease processes.

GABAergic System Deficiency

• GABA transaminase (GABA-T) deficiency, a genetic disorder, leads to recurrent seizures, uncontrolled movements and other complications in infants.
• Symptoms are present early in infancy.
• These patients have difficulty thriving and developing.

Embryonic Nervous System and GABA/Glycine

• GABA and glycine can cause depolarization in the embryonic nervous system, which contrasts to their inhibitory role in the adult nervous system.
• In early stages of development, GABA can affect neuron activity in an excitatory way.
• This early excitatory role is essential for CNS development.

Receptor Modulation

• Glycine receptors are allosterically modulated.
• Alcohol impacts glycine receptors and GABA receptors in different ways.

Additional Notes (from various pages)

• Strychnine: a substance historically used as a performance enhancer, now forbidden in sports competition due to its convulsive properties.
• Several case studies provide historical examples of substances used or abused in the past in an attempted performance enhancement which often highlighted ethical considerations.
• Learning Outcomes: Specific outcomes mentioned include discussing various transmitters, their actions, and agonists/antagonists, along with examining associated diseases and case studies.
• There's a specific concern with learning outcomes tied to performance enhancement.
• The pharmacology of GABA and glycine is crucial for understanding diverse neurological and psychiatric conditions.

Test your knowledge on glycine transporters GLYT1 and GLYT2, their functions, and their role in conditions like hereditary hyperekplexia. This quiz covers key concepts related to glycine regulation at the synapse and the implications of transporters in neurological function. Challenge yourself with a variety of true/false questions and in-depth inquiries.