S377 Chapter 13

Sometimes cells communicate directly through ❌, which connects the ❌ of the cells and allows small molecules to travel through. This is different from normal signalling.
❌ signalling involves signalling molecules not being ❌, but expressed on the ❌ of the cell, and picked up by ❌ on the plasma membrane of another cell. For example, when ❌ are presented to ❌ in the ❌.

❌ affects local cells. Cells closer to the source react differently to those further away due to ❌. Signalling molecules used are either rapidly taken up by target cells or degraded by ❌ to keep the effects limited to a small area.
❌ is an oddity, and may occur in ❌ to allow them to keep growing inappropriately. Also happens in ❌.
❌ involves signalling cells very far away, with the signalling molecules often transported in the ❌. These signalling molecules are called ❌ (though there is lots of variation) and are not ❌ so last longer than ❌.
❌ involves neurons, where the signal is transmitted electrically along ❌ before being turned into a chemical signal at ❌, to cross the ❌. The chemicals signalling molecules are called ❌ (these are also very varied).

In a basic model of ❌, a signalling molecule binds to a ❌, and this activates a sequence (or web) of ❌ that spread the information to relevant parts of the cell, activating ❌, which effect a ❌.

There are four types of cell surface receptors: ion ❌ receptors, 7-❌ receptors, receptors with ❌ activity, and enzyme-associated (❌) receptors. Receptors with intrinsic ❌ activity are mostly ❌.

Two basic categories of signalling molecules intervene in signal transduction, according to the spatial and temporal requirements of the signalling pathway.
(a) Small diffusible signalling molecules (‘❌’) enable rapid signal ❌ and a ❌ cellular response.
(b) Signalling ❌ fulfil many roles (by virtue of protein–protein interaction and protein regulation), including signal ❌, modulation, t❌ and a❌ functions.

❌ and proteins activated by ❌ on tyrosine, serine and/or threonine residues can act as ❌.

The ❌ of the signalling protein is critical to its ❌, and this is aided by ❌ or preassembled ❌.

Specific binding of ❌ to each other is critical for the effective ❌ of the signal. ❌ allow transient binding to ❌ (often phosphorylated) amino acid sequences or to ❌.

Ligands are classed as agonists or antagonists.
❌ usually work by binding to the ligand binding site and ❌ its ❌. ❌ bind to the receptor, but ❌ the switch to the active conformation.
A single receptor may be able to bind several ❌, and a single ligand may be able to bind to ❌.

❌ comprise a limited number of ❌, which determine ❌ and specificity of receptor–ligand complexes. Some ligands bind to ❌ and some receptors bind to ❌.

❌ is a good example of a ligand with two structurally different kinds of ❌. ❌ receptors are ion channels, which are found predominantly in ❌, and are stimulated by nicotine. Nicotinic receptor ❌ include the toxins α -bungarotoxin and tubocurarine. Acetylcholine binds at two sites within the channel. ❌ receptors, in contrast, are ❌, found (for example) in ❌. Muscarine acts as an ❌, whereas ❌ acts as an antagonist. Acetylcholine binds in the core region of the transmembrane helical segments.

❌ has a range of structurally related ❌, with different tissue distributions and different ❌ for numerous agonists and antagonists. Adrenalin, like acetylcholine, binds in the ❌ of the receptor, though other GPCRs can be activated in a variety of ways.

Mechanisms for ❌ are varied and include ❌ changes (ion-channel receptors and 7TM), ❌ (receptors with intrinsic enzymatic activity and recruiter receptors) or even proteolysis.

For most ❌ (the exception being the Frizzled class of 7TM receptors), ❌ on ligand binding activates associated ❌. Hence, they are called ‘❌’.

Receptors with ❌ include ❌, receptor serine–threonine kinases, receptor tyrosine phosphatases, and receptor guanylyl cyclases. Most RTKs are activated by ❌ on ligand binding, leading to ❌ of the cytoplasmic portion of the receptor. ❌ tyrosine residues serve as docking sites for SH2-containing signalling proteins, which also recognize sequence-specific flanking motifs.

❌ of ❌ facilitates the interaction between the ❌ receptor and ❌ with intrinsic enzymatic activity such as ❌.

Receptors can be ❌ by ❌ of the ❌, or by receptor ❌, which can be by i❌, by s❌ or by d❌ of the receptor.

Some ❌ can diffuse across the ❌, and so have ❌, rather than cell surface receptors. Small hydrophobic ligands such as ❌ bind to members of the ❌, which undergo ❌ and bind to specific ❌, stimulating ❌ of target genes.

❌ are tethered to the ❌ of the plasma membrane, and are activated by ❌ within ❌.
There are many different ❌ (and a few βγ subunits), which interact with ❌ and different ❌.
The major targets of G proteins include ion ❌, ❌ (❌ by Gαs and ❌ by Gαi) and PLC- β (activated by Gαq).

❌ is the precursor of a family of small lipid ❌. The inositol ring can be further ❌ at positions 3, 4, and 5 by lipid kinases. ❌ specializes in phosphorylating the hydroxyl group at the ❌, thus generating the active signalling molecules PI(3,4)P2 and PI(3,4,5)P3 . The ❌ is recognized as a docking site by ❌, thus providing a mechanism for signalling proteins to be recruited to the membrane.

❌ (especially PLC- β , activated by ❌, and ❌ PLC- γ ) cleave PI(4,5)P2 to generate ❌ and inositol 1,4,5-triphosphate (IP3 ).
DAG remains embedded in the ❌, where it activates ❌.
❌ diffuses through the cytosol, and opens ❌, releasing ❌ into the cytosol.

The ❌ is an important ❌, which enters the cytosol from the ❌ through specific channels on the plasma membrane, or is rapidly released from ❌ into the cytoplasm.
Calcium channels include ❌ calcium channels, ❌dependent calcium channels, or ryanodine receptors in skeletal muscle cells.
It activates numerous Ca2+ -dependent proteins, ❌, but many of its effects are mediated via ❌, which has four allosteric Ca2+ binding sites.
Ca2+ /calmodulin then binds to and regulates ❌, especially Ca2+ /calmodulin-dependent protein kinases (❌).

❌ is another important ❌, synthesized from ❌ by ❌ (which is activated or ❌ by different G protein subtypes). It can open cAMP-gated ❌, but it mediates many of its effects through cAMP-dependent protein kinase A (❌), whose roles include regulating ❌ metabolism, and ❌ of a transcription factor (❌) that binds to the ❌.

❌ is synthesized by guanylyl cyclase. Its targets include ❌ ion channels and a ❌.

❌ is the archetypal ❌, or small, ❌. Ras classically operates downstream of ❌: Grb-2, an SH2/SH3-containing adaptor protein, binds to phosphotyrosines on the activated RTK, and recruits Sos to the membrane environment; Sos promotes GTP binding by Ras.
❌ has more than one target, including ❌, but its most important downstream pathway is the ❌. Activated Ras recruits ❌ to the membrane, where it is activated and then ❌ MEK, which then phosphorylates ERK, a ❌. These have multiple cytoplasmic and ❌ targets involved in cell ❌ or differentiation.

❌ involved at various points in signalling pathways include ❌ (for example, the EGF receptor), non-receptor ❌ (such as Src and JAK), serine❌ such as PKC, PKA, MAP kinases and the TGF receptor, and rare ❌ such as MEK.

❌ dephosphorylate proteins, and are grouped according to their targets, as are protein kinases. They include protein tyrosine ❌, ❌ phosphatases, and a few dual-specificity phosphatases.

The duration of ERK activity determines ❌ of different ❌ (SRF/TCF for immediate early genes; AP-1 for other target genes).

❌ metabolism is controlled by two enzymes, glycogen ❌ (mediating glycogen synthesis) and ❌ (mediating glycogen breakdown).

❌ pathways converge in the regulation of ❌: cAMP/PKA and GSK-3β are ❌ regulators, whereas ISPK/PP1G ❌ regulate the activity of glycogen synthase.

❌ and adrenalin have opposite effects on glycogen ❌: insulin ❌ glycogen synthesis by activating ISPK/PP1G and by inhibiting GSK-3β by the ❌ pathway, whereas ❌ inhibits glycogen synthase by the ❌ pathway.

Three pathways converge in the activation of ❌ by phosphorylase ❌: Ca2+ and ❌ activate phosphorylase kinase, whereas ❌ is a negative regulator.

❌, adrenalin and ❌ promote ❌ breakdown, whereas ❌ inhibits it.

❌ in skeletal muscle and ❌ in liver activate ❌ kinase by a common mechanism, an increase in cytosolic ❌ , although the effect of ACh is by ❌ channels and that of adrenalin by ❌ channels.

❌ in muscle and ❌ in liver activate ❌ kinase by a common mechanism, namely an increase in ❌ and subsequent activation of ❌. In addition, PKA further activates phosphorylase kinase in skeletal muscle by inhibition of ❌ either directly or indirectly.

❌ has an opposite effect to ❌ on ❌ breakdown, namely the ❌ of glycogen breakdown by ❌ of the phosphorylase kinase inhibitor, ❌.

Activated ❌ activates ❌, which exerts a number of anti-apoptotic actions by ❌ of downstream proteins: (1) it phosphorylates ❌, thereby promoting Bad’s ❌ by an adaptor protein (not shown); (2) it phosphorylates and thereby ❌ (in humans); (3) it phosphorylates and thereby ❌ members of the Forkhead family of ❌, which stimulate transcription of ❌; and (4) it phosphorylates and thereby ❌ the transcription factor ❌, which stimulates transcription of ❌.