Question

Describe the heptahelical receptor endocytic pathway, including characteristics of ligand, receptor, and interactions with effector molecules involved in the receptor-mediated internalization for either recycling or lysosomal targeting and explain how these pathways affect GABA-mediated inhibition of neuronal excitability. Include an explanation on how GABA A and GABA B receptors differ.

Answer 1

Answer- G protein-coupled receptors (GPCRs) also called heptahelical receptor because it contains seven transmembrane proteins are a large family of cell surface receptors that share a common structure and method of signaling. The members of the GPCR family all have seven different protein segments that cross the membrane, and they transmit signals inside the cell through a type of protein called a G protein. GPCRs are in diverse forms and they bind to many different types of ligands. G proteins come in different types, but they all bind the nucleotide guanosine triphosphate (GTP), which they hydrolyze to form GDP. A "G protein" attached to GTP is active, or “on,” while a G protein that’s bound to GDP is inactive, or “off.” The G proteins that associate with GPCRs are a type made up of three subunits, known as heterotrimeric G proteins. When they’re attached to an inactive receptor, they’re in the “off” form (bound to GDP).

When the ligand binds to GPCR, they get activated and cause the G protein to exchange GDP for GTP. The now-active G protein separates into two pieces (one called the α subunit, the other consisting of the β and γ subunits), which are freed from the GPCR. The subunits can interact with other proteins, triggering a signaling pathway that leads to a response.

Eventually, the α subunit will hydrolyze GTP back to GDP, at which point the G protein becomes inactive. The inactive G protein reassembles as a three-piece unit associated with a GPCR. Cell signaling using G protein-coupled receptors is a cycle, one that can repeat over and over in response to ligand binding.

Types of ligands

Ligands, which are produced by signaling cells and interact with receptors in or on target cells, come in many different varieties. Some are proteins, others are hydrophobic molecules like steroids, and others yet are gases like nitric oxide. Here, we’ll look at some examples of different types of ligands.

Ligands that can enter the cell

Small, hydrophobic ligands can pass through the plasma membrane and bind to intracellular receptors in the nucleus or cytoplasm. In the human body, some of the most important ligands of this type are the steroid hormones.

Familiar steroid hormones include the female sex hormone estradiol, which is a type of estrogen, and the male sex hormone testosterone. Vitamin D, a molecule synthesized in the skin using energy from light, is another example of a steroid hormone. Because they are hydrophobic, these hormones don’t have trouble crossing the plasma membrane, but they must bind to carrier proteins in order to travel through the (watery) bloodstream.

Ligands that bind on the outside of the cell

Water-soluble ligands are polar or charged and cannot readily cross the plasma membrane. So, most water-soluble ligands bind to the extracellular domains of cell-surface receptors, staying on the outer surface of the cell.

Peptide (protein) ligands make up the largest and most diverse class of water-soluble ligands. For instance, growth factors, hormones such as insulin, and certain neurotransmitters fall into this category.

Types of receptors

Receptors come in many types, but they can be divided into two categories: intracellular receptors, which are found inside of the cell (in the cytoplasm or nucleus), and cell surface receptors, which are found in the plasma membrane.

Now, GABA is a chief inhibitory neurotransmitter. Two general classes of GABA receptor are known:

• GABA_A in which the receptor is part of a ligand-gated ion channel complex
• GABA_B , which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins)

GABA_A receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero.

GABA_B receptors transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium channels. GABA_B receptors also reduces the activity of adenylyl cyclase and Ca²⁺ channels by using G-proteins with G_i/G₀ α subunits.