Calcium Signaling and GPCR Proteins

The process of cells using calcium ions (Ca2+) as a messenger to relay signals and trigger various cellular responses.

Calcium acts as a second messenger in signal transduction, carrying information within the cell to regulate various processes like muscle contraction, gene expression, and cell growth.

The maintenance of a stable and balanced concentration of calcium ions (Ca2+) within the cell, essential for normal cellular function.

A specific signaling pathway involving G-protein coupled receptors (GPCRs) that uses the Gαq protein to activate phospholipase C (PLC), ultimately leading to increased intracellular calcium.

A calcium-binding protein that acts as a molecular switch, changing its shape and function upon binding calcium. It activates various downstream proteins.

A structural motif found in calcium-binding proteins. It's a helix-loop-helix structure that coordinates a calcium ion. This motif allows for the binding of calcium, a crucial step in intracellular signaling.

A type of protein kinase that is activated by the binding of calcium and calmodulin. These enzymes play a role in many cellular processes, including learning and memory.

Calmodulin, a small, ubiquitous protein, acts as a calcium sensor in the cell. When calcium binds to it, it undergoes a conformational change that allows it to activate other target proteins. This activation can occur through different mechanisms, like exposing catalytic sites, altering conformation, or even forming a new protein complex.

Calmodulin in its inactive state, meaning it's not bound to calcium. In this form, its central helix is shielded by terminal helices. This prevents it from interacting with target proteins.

Calmodulin in its active state, bound to calcium. This leads to conformational changes, exposing hydrophobic patches that are essential for recognizing target proteins. The central helix is now exposed and ready to interact.

When calmodulin binds to its target protein, it undergoes further changes: the central helix unwinds and forms a hinge, the molecule bends around the target, and the N and C terminals interact through their hydrophobic regions. This interaction resembles two hands holding a rope.

After binding to a target protein, calmodulin can activate it through different mechanisms. This can be done by exposing the catalytic site, changing the target's conformation, or inducing its dimerization. Overall, calmodulin acts as a signaling hub, regulating various cellular functions.

Auto-inhibition domain, a region in a protein that prevents its activity until it is relieved by a specific signal.

Calcium-calmodulin-dependent kinase II, an enzyme that is activated by a signaling cascade involving calcium and calmodulin.

CaM Kinase II has four activity states, determined by a combination of protein binding, ion binding, and phosphorylation.

CaM kinases I-IV, phosphorylase kinase, and myosin light chain kinase all interact with calmodulin and convert calcium signals into phosphorylation signals.

A mechanism of enzyme activation where a molecule binds to the enzyme and changes its shape to create an active conformation.

An enzyme that is activated through active site remodeling, a specific example of how this process works.

Regulators of G-protein signaling, proteins that regulate G-protein signaling by accelerating GTP hydrolysis.

RGS proteins enhance the affinity of Gα subunits for βγ after GTP hydrolysis, speeding up the reformation of the heterotrimer, thus slowing down G-protein signaling.

The 3D arrangement of atoms in RGS and Gα proteins, revealing contact points between conserved residues. This contact is crucial for their interaction and signaling.

A family of enzymes that phosphorylate the agonist-occupied G protein-coupled receptor (GPCR), initiating a cascade of events leading to receptor desensitization and uncoupling from G proteins.

GRKs phosphorylate the agonist-occupied GPCR, causing it to uncouple from G proteins. This reduces the receptor's signaling ability, leading to desensitization.

The β2-adrenergic receptor can be phosphorylated by both protein kinase A (PKA) and GRKs. Phosphorylation by GRKs leads to desensitization, while PKA phosphorylation contributes to downstream signaling.

GRKs have a complex structure with distinct domains for: GPCR binding, membrane anchoring, RGS interaction, catalytic activity, and interaction with CaM and Gβγ.

GRKs are regulated by various factors, including phosphorylation by kinases (such as PKC), binding to agonist-occupied receptors, and interaction with calcium-binding protein (CaM) or lipids.

There is no specific amino acid sequence that GRKs always phosphorylate. However, they show a general pattern of targeting Ser/Thr residues.

The lack of a specific consensus sequence for GRK phosphorylation makes it challenging to develop a specific inhibitor that targets a particular GRK.