Introduction
G
Protein-Coupled Receptors (GPCRs) are membrane proteins that enable cells to
communicate with each other. They function as molecular switches that convert
extracellular signals (e.g. hormones, neurotransmitters etc) to intracellular
responses (e.g., sensory responses, immunological responses,
neurotransmission). GPCRs have seven distinct trans-membrane domains and play a
role in many physiological processes. GPCRs are activated by ligands,
triggering downstream signaling cascades through second messengers.
The structure of G protein-coupled receptors
GPCRs are
integral membrane proteins that have seven trans-membrane alpha-helical
domains. The detailed structure is discussed below:
1) Trans-membrane Domains (TMDs)
There are Seven
Hydrophobic Trans-membrane Alpha-helical (TMD) domains that span the cell
membrane’s lipid bilayer. The TMDs are connected to each other by alternating
extracellular and intracellular loops. The receptor's N-terminus is normally
found on the extracellular side, whereas the C-terminus is found on the
intracellular side.
2) Extracellular Loops
The
extracellular loops that link the trans-membrane domains on the extracellular
side of GPCRs vary in length and sequence. They frequently have crucial ligand
binding sites. Ligands like as neurotransmitters and hormones interact with
these loops to activate the receptor.
3) Intracellular Loops
On the
intracellular side, intracellular loops connect the trans-membrane domains.
When a receptor is activated, these loops interact with intracellular signaling
proteins such as G proteins and Arrestins to begin downstream signaling
processes.
4) Ligand-Binding Pocket
There is a
distinct ligand-binding pocket or cavity within the trans-membrane domains
where ligands bind. This interaction causes a conformational change in the
receptor, which activates it.
5) G Protein Interaction Site
The GPCR has an
intracellular area where it interacts with G proteins. When a ligand binds to a
receptor, it causes a conformational change that permits the ligand to activate
the associated G protein by facilitating the exchange of GDP for GTP on the
alpha subunit of the G protein.
6) C-Terminal Tail
The receptor's
C-terminal tail is normally found on the intracellular side and may contain
phosphorylation sites. Phosphorylation of these locations can influence
receptor activation as well as its interactions with downstream signaling
proteins.
7)
Post-translational Modifications
GPCRs can
undergo various post-translational modifications, including glycosylation,
phosphorylation, and palmitoylation, which can affect their stability,
localization, and signaling capabilities.
8) Oligomerization
Some GPCRs can
form dimers or higher-order oligomers with other GPCRs, affecting their
pharmacological characteristics and signaling results.
9) Conformational Changes
The
conformational change that happens upon ligand binding is the defining feature
of GPCR activation. This modification is carried from the ligand-binding site
to the intracellular side, where it interacts with G proteins and other signaling
proteins to trigger downstream signaling processes.
Functioning of GPCR
G
Protein-Coupled Receptors (GPCRs) work in a complex and highly regulated
manner, enabling cells to interact with a wide variety of signals from the
extracellular compartment. Here’s a brief overview of GPCRs:
1) Ligand Binding
GPCRs are found
on the cell membrane and function as receptors for external signaling molecules
such as neurotransmitters, hormones, or sensory inputs (for example, light in
the case of visual GPCRs). Each GPCR is unique to a different ligand. When a
ligand attaches to the receptor's extracellular domain, it causes the receptor
to alter conformation.
2) Conformational Change
Ligand
interaction causes a conformational change in the GPCR, which is conveyed from
the extracellular to the intracellular side via the receptor's seven trans-membrane
domains. This conformational shift is an important step in GPCR activation.
3) G Protein Activation
The activated
GPCR may now interact with a family of intracellular proteins known as G
proteins. G proteins are made up of three subunits α, β, and γ. The subunit is
attached to GDP (Guanosine di-phosphate) in its inactive form. When the GPCR is
active, it catalyses the subunit's exchange of GDP for GTP ( Guanosine tri-phosphate).
4) G Protein Dissociation
When GTP
attaches to a subunit, it experiences a conformational shift, leading it to
dissociate from the subunits. These two subunits are now free to interact with
effector proteins downstream.
5) Effector Protein Activation
Depending on
the exact GPCR and G protein involved, the free subunit and subunits of the G
protein can activate various downstream effector proteins. Examples of effector
proteins include:
· Adenylate
cyclase: Some
GPCRs activate adenylate cyclase, which is an enzyme that converts ATP
(adenosine triphosphate) to cyclic AMP (cAMP). cAMP acts as a second messenger,
activating protein kinase A (PKA) and regulating a variety of cellular
activities.
· Phospholipase C: Phospholipase C (PLC) is activated by other GPCRs, resulting in the synthesis of inositol triphosphate (IP3) and diacylglycerol (DAG). DAG stimulates protein kinase C (PKC), which regulates cellular responses by releasing calcium ions from intracellular reserves.
· Ion Channels: Some GPCRs
have a direct effect on ion channels by regulating ion flow and membrane
potential, which can affect neuronal signaling or muscle contraction.
6) Signal Propagation
The activation
of effector proteins sets off a chain of intracellular processes, generally
including phosphorylation and dephosphorylation reactions, that eventually lead
to particular physiological responses. Changes in gene expression, changed
enzyme activity, and ion channel modification are examples of these reactions.
7) Signal Termination
GPCR signaling is closely controlled. It can be terminated by a variety of methods, including the hydrolysis of GTP to GDP on the G protein subunit, allowing the subunit to reassociate with the subunits. Furthermore, receptors can be phosphorylated by kinases, resulting in desensitisation and internalisation, which further dampens the signaling response.
