5. Signaling molecules and receptor

Types of signalling molecules

neurotransmitters
hormones
local mediators

Neurotransmitters

Chemicals released from nerve terminals that combine with specific receptors on target cells

Hormones

Specialized endocrine cells secrete hormones into the bloodstream to travel to distant regions and elicit a response

Local mediators

Chemicals that act locally on cells in their immediate environment
Not in blood

Local mediators are typically made of

peptides and are rapidly destroyed or removed.

Examples of local mediators

growth factors
cytokines (interferon, interleukin)
prostaglandins
histamine

1st messengers

are signaling molecules such as hormones or neurotransmitters that bind to receptors to initiate a cellular response.

Autocrine signalling

a cell secretes local mediators that act on itself

Gap junction signaling

involves direct communication between adjacent cells through specialized channels called gap junctions, allowing the transfer of ions and small molecules.

paracrine signaling

is a form of cell signaling in which a cell produces a signal to induce changes in nearby cells, affecting their behavior.

Paracrine signalling is mediated by

both local mediators and neurotransmitters

Endocrine signaling

is a type of cell signaling where hormones are secreted into the bloodstream to target distant cells, regulating various physiological processes.

Receptor

a molecule (such as a protein) that has an affinity for a specific ligand, where activation is coupled to a process to evoke a response

Ligand

Signalling molecule that binds to a receptor

Intracellular receptor

is a type of receptor located inside the cell, usually within the cytoplasm or nucleus, that binds to ligands that can pass through the cell membrane, such as steroid hormones.

Intracellular receptor ligands

lipid-soluble/hydrophobic which easily diffuse across cell membranes and make a complex with the receptor (most function as transcription factors)

Examples of intracellular receptor ligands

• steroid hormones (cortisol, progesterone, testosterone)
• vitamin D
• retinoic acid

cell surface receptor

is a receptor located on the cell membrane that binds to ligands, initiating a response via signal transduction pathways.

Cell surface receptor ligands

are hydrophilic and cannot cross plasma membrane

3 main types of cell surface receptors

ion-channel receptors,
G-protein coupled receptors,
enzyme-linked receptors.

ion-channel receptors

membrane receptors contain an ion channel whose open or closed state is gated by the binding of a ligand to the receptor

Signaling ligan for ion channel linked receptors is often

a neurotransmitter that binds and causes the ion channel pore to open and allow ions to flow across membrane

ione channel linked receptors are aka

Ligand-gated ion channels
Ionotrophic receptors

Example of ion channel linked receptors

include the nicotinic acetylcholine receptor (nAChR)

NIcotinic receptor (nAChR) ligand

acetylcholine

Nicotinic receptor mechanism (nAChR)

two ACh molecules binds to receptors, the ion channel pore opens, allowing Na+ to move intracellularly. The channel is also permeable to K+ ions, which exit the cell.

Overall, activation of nicotinic receptors causes

depolarization of the postsynaptic membrane, leading to excitation of the neuron or muscle cell. (Na in, K out)

Where are nicotinic receptors found

• Neuromuscular junction (NMJ)
• Autonomic nerve ganglia
• CNS
• Adrenal medulla

G protein coupled receptors

large family of cell receptors which have 7 transmembrane segments that are associated with G proteins

G protein coupled receptors are aka

G protein-linked receptors
Trimeric G-protein-coupled receptors
Metabotropic receptors

Examples of GPCR

• muscarinic receptors
• alpha & beta adrenergic receptors
• dopamine receptors

1st step of GPCR activation

signaling molecule binds to extracellular g-protein segment and alters the conformation

Once the ligand has bound extracellular to GPCR, when what

activation causes GDP to be exchanged for GTP on the G-protein.

Once GTP is bound the GPCR then what

GTP-bound α-subunit and the βγ complex can interact with other molecules to mediate a diverse variety of signaling responses in the cell.

ONce GTP is hydrolyzed to GDP then what

signalling is terminated, the trimeric G protein reassociates.

Which subunit of g-protein hase GTPase activity

The alpha subunit

Activated G protein mechanisms

activation of effector enzymes
activation of 2nd messengers
Stimulate transcription
directly activate ion channels

Examples of G-protein activated effector enzymes

• adenylate cyclase: cAMP pathway
• phospholipase C: IP3-DAG pathway

Overall, effector enzymes produce

second messengers that propagate signaling pathways, leading to various cellular responses.

Second messengers

intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules.

Examples of second messengers

cyclic AMP (cAMP)
cyclic GMP (cGMP)
inositol triphosphate (IP3 )
diacylglycerol (DAG)
Ca2+

The G protein complex is often categorized by

type of α subunit present

Gα_s

G protein that stimulates adenylyl cyclase

Gα_i

G protein that inhibits adenylyl cyclase

Gα_o

closes calcium channels

Gα_t

G protein involved in visual phototransduction, stimulating cGMP phosphodiesterase.

Gα_q

G protein that activates phospholipase C

classic example of GPCR

muscarinic receptor

Ligand for muscarinic receptors

acetylcholine

function of muscarinic receptors

Mediate parasympathetic nerve control in different tissues and organs.

Does Ach ligand always have excitatory effects

no, acetylcholine can have both excitatory and inhibitory effects depending on the G protein type (Gs Gq and Gi) or receptor type (muscarinic/nicotinic)

Enzyme linked receptors

possess both enzymatic (catalytic) and receptor functions.

Enzyme linked receptors: ligand binding domain

found on extracellular surface and generally binds growth factors and cytokines

Enzyme linked receptors: transmembrane domain

composed of a region of hydrophobic amino acids that span the cell membrane.

Enzyme linked receptors: enzymatic (catalytic) domain

on intracellular surface and has intrinsic enzymatic activity, usually kinase`

Examples of enzyme linked receptors

include receptor tyrosine kinases, serine/threonine kinases, receptor guanylyl cyclases, and tyrosine phosphatases

When a ligand binds to the extracellular domain of a enzyme-linked receptor, then what

conformational change (dimerization) to transmembrane proteins

COnformational change of transmembrane protein (enzyme linked) results in

Intrinsic enzymatic activity occurs (phosphorylation often) —> leads to 2nd messengers and signaling cascades

Enzyme linked response speed

typically slow and usually require many intracellular signaling steps.

Neurotransmitters

signalling molecules released by neurons stimulated by electrical signals (action potentials)

Neurotransmitter bind to which type of receptors

cell surface receptors since they are hydrophilic
ion channel linked OR g protein coupled receptors

1Primary chemical signals (neurotransmitters) in the ANS

Ach and NE

Most common examples of nuerotransmitters

Norepinephrine (NE)
Epinephrine
Dopamine
Acetylcholine (ACh)
Serotonin (5-HT)
Histamine
Glutamate
γ-aminobutyric acid (GABA)
Opioids (endorphin, enkephalin)

Somatic NTs

Ach and NE

Parasympathic primary nts

Ach

Neuropeptides are synthesized via

transcription and translation in ER of the nerve cell body; packaged into secretory granules; then transported to the nerve terminal by fast axonal transport

Examples of neuropeptides

endogenous opioids, endorphins

Neurotransmitters are synthesized

and packaged into synaptic vesicles in pre-synaptic nerve terminals

Ach synthesis occurs in

presynaptic nerve terminal by choline acetyltransferase and involves the enzymatic reaction of acetyl CoA with choline.

Ach is degraded by

acetylcholinesterase in the synaptic cleft, which hydrolyzes it into acetate and choline.

Catecholamines

neurotransmitters derived from tyrosine

Catecholamines examples

• dopamine
• DOPA
• norepinephrine (NE)
• epinephrine (E)

Biosynthetic pathway of catecholamines

conversion of tyrosine —> DOPA, —> dopamine —> norepinephrine —> epinephrine.

Catecholamines (neurotransmitter version) are produced, stored and released from

nerve terminals

Catecholamines (hormone version) are produced, stored and released from

adrenal medulla

Serotonin (5-HT) synthesis

made in presynaptic nerve terminal from TRYPTOPHAN

CNS synapse

is the junction between two neurons in the central nervous system where neurotransmitters are released and received, facilitating communication.

Major excitatory neurotransmitter of the CNS

glutamate

Glutamate can bind to which 2 glutamate receptors

ionotropic —> excitatory electrical signal
GPCR —> 2nd messenger cascade

Neuromuscular junction

synapse between a somatic nerve motor neuron and a skeletal muscle fiber

NMJ neurotransmitter is always

Ach

Where do neurotransmitters act with the ANS

autonomic nerves

Autonomic nerves are divided into 2 groups based on neurotransmitter, what are they

adrenergic and cholinergic

Adrenergic nerves

When transmission of nerve impulses is mediated by NE and E

Adrenergic nerves can be which type of receptor

alpha or beta but ALL ARE G PROTEIN COUPLED

Cholinergic autonomic nerves

Nerves that use acetylcholine for neurotransmission in the autonomic nervous system.

Cholinergic nerve receptor types

are primarily muscarinic (ligand gated ions channels) and nicotinic receptors (GPCR)

alpha1 adrenergic receptors

predominant receptor in vascular smooth muscle. —> Net effect is arteriolar smooth muscle contraction (activated by NE/E)

NE (or E) binding to alpha1 receptor (GPCR) activates

the phospholipase C pathway, leading to increased intracellular calcium and muscle contraction.

NE signaling at alpha2 adrenergic receptors

activates a Gi- protein decreases adenylate cyclase activity —> net effect is inhibitory

NE signaling at beta1 adrenergic receptors

activates a Gs- protein • increases adenylate cyclase activity • increases cAMP—> net effect is excitatory, leading to increased heart rate and contractility.

3 types of hormones

peptide hormones, steroid hormones, and amino acid-derived hormones.

peptide hormones

often synthesized by translation, process in ER, then packaged and released in response to stimulus

Peptide hormone examples

Insulin •
antidiuretic hormone •
oxytocin •
follicle-stimulating hormone

Amino acid derived hormones

small hormones made from amino acid tyrosine or tryptophan and stored in endocrine cells until needed

examples of amino acid hormones

catecholamines (E and NE - synthesized in adrenal medulla)
• thyroxine (T4, thyroid gland)
• melatonin (pineal gland)

Steroid hormones

Derived from modification of cholesterol in the adrenal cortex, gonads and placenta. Synthesis occurs in mitochondria and smooth ER.

steroid hormone signalling

lipid soluble and thus can diffuse into a cell membrane and nucleus —> intracellular receptors

How are steroid hormones transported

via carrier proteins since they are water insoluble

Examples of hormone carrier proteins

• corticosteroid binding globulin
• sex hormone binding globulin
• thyroxine-binding globulin
• albumin (non specific)