Cellular Communication and Signal Transduction

organism cells must be able to communicate with each other to

maintain homeostasis

respond to changes (allostasis)

regulate growth, cell division, and development into tissues

coordinate their specific cell function

Cells communicate using

Ligands- a hormone or neurotransmitter that binds to specific receptor on cell surface/inside cell

what are the 3 main ways cells communicate

membrane bound receptors (proteins)

receptor proteins located INSIDE the cell

Gap junctions that coordinate the activities of adjacent cells

what type of cells use gap junctions

cells in direct contact w neighbor cells linked by their plasma membrane= cell junctions

neuro, cardiac cells

function of cell junctions:

hold cells together= tight junction (BBB to precent toxins entering CNS)

attachment= adherens junctions (cardiomyocytes together), desmosomes(skin cells), hemidesmosomes

Provide chemical communication= gap junctions (Na, K, Ca for cardiomyocyte contraction)

Gap junctions are found in…

tissues where synchronized functions are required

cardiac muscle cell-contrxion

Smooth muscle cells in blood for vascular tone

Intestinal cells for peristaltic movement

neurons for nerve conduction

Autocrine signaling:

cell responds to molecule that THEY produce and secrete

growth factors=proteins= cell proliferation (cancer)

immune cells= self proliferation= T cells

Paracrine signaling:

secreted by a cell into a local environment that are sent to cells in immediate area (short distances)

sxnals secreted in local environments get rapidly destroyed, which is why only those in immediate are get affected

neurotransmitters, Histamine, Growth factors, Inflammatory cytokines

Endocrine signaling:

signal done by endocrine cells that secrete hormones that travel bloodstream “it is way out”

sxnaling accomplised at distant sites

Contact dependent (Juxtracrine) signaling:

signal ligand is NOT secreted, instead it is membrane bound and interacts directly with the receptor of target cell

requires cells to be in close contact

works in the immune system, helper T cells bind to antigen presenting protein on B cell surface. It activates B cell to become a memory B cell or plasma cell= antibodies produced

3 stages of cell signaling:

reception- ligan bind to specific receptor at cell surface

Transduction- signal/instructions from ligands are conveyed to interior of target cell

Response- cellular response from the binding of ligand to receptor

who uses signal transduction and how does it work?

Hydrophilic cells since they CANT go straight through plasma membrane

it is the process by which a message from outside a cell(ligand) is transmitted through the interior to yield a response

it is very specific for a ligand= very specific for a particular receptor

you need to know composition of cell membrane to understand signal transduction

Siganling molecules can be…

hydrophobic or hydrophilic

Hydrophobic ligands must have

transport proteins to travel in EC space, and it can diffuse across cell membrane directly to bind to receptor within the cell cytoplasm or nucleus

“Karens want to see the manager! they go straight in” = NO SECOND MSGER NEEDED

What are examples of Karens that go straight through and bind to receptors within cell cytoplasm or nucleus?

steroid hormones, thyroid hormones, testosterone, estrogens, progesterone, aldosterone, cortisol → they bind to specific genes to regulate their activity

STEROID HORMONES TAKE A WHILE TO CAUSE A CELLULAR/METABOLIC RESPONSE, BUT LAST LONG

(this is why thyroid meds take a bit to work)

hormone receptor complex acts as

transcribing factors, turning certain genes on and off, affecting production of a specific protein!

Hydrophilic Ligands/Signaling

Most signals molecules are hydrophilic and can travel unbound in EC fluid!!

BUT CANNOT cross plasma membrane directly (phospholipid mem, duh)

Thus, to pass their signal they must bind to transmembrane protein on cell surface

THIS CELLULAR RESPONSE IS MORE RAPID BUT SHORT LIVED

What is the 1st and 2nd part of transmembrane proteins

the EC end that binds the ligand

the IC end that triggers a signaling pathway inside the cell

What are the 3 major classes of cell surface receptors

Ion channel receptors

enzyme coupled receptors

G protein coupled receptors

Ion channel receptors- ligand gated ion channel

found in almost all cells but are prevalent in nerve and muscle cells “excitable cells” bc it allows cells to RAPIDLY respond to external stimuli

LIGAND GATED ION CHANNELS OPEN in direct response to specific ligand like a neurotransmitter

allows ions like Na, K, Cl, Ca to flow down concentration gradient

Voltage gated ion channel - ion channel receptor

channels open in response to change in membrane potential allowing specific ions to pass leading to a cellular response

voltage sensor attached to ion channels

directionally propagate electrical signals

how do ligand gated channels and voltage channels work together?

ligand binds → ligand channel opens → Na goes in → CM is less - → voltage channel opens → more ions go in

Mechanically gated ions- ion channel receptors

open in response to mechanical forces or physical deformation (ex: pressure)

by opening in allows influx or efflux of ions across CM that triggers downstream signaling pathways. Created action potential that transmit to CNS for processing of the sensations

ex: responding to touch, vibration, or pressure

Second Messengers:

used by hydrophilic ligands

the first messenger issues orders by binding w receptors on surface and triggers the “pass it on”

second messengers are NONPROTEIN molecules/ions like cAMP, IP3, DAG, or calcium

Relay and Diffuse, Amplify, Execute

Enzyme couples receptors:

catalyze enzyme rxns when they are activated by ligand

THEY FUNCTION AS AN ENZYME, nearly all as protein kinases= they mediate phopshate group from ATP to proteins, aka phospholyration

^ which activated various proteins leading to wide range of cellular processes

what are the 3 main types of enzyme couples receptors?

receptor Tyrosine Kinases

tyrosine kinase associated receptors

receptor serine/threonine kinases

Receptor Tyrosine Kinases

most common and largest

Have intrinsic activity= they can phosphorylate themselves when activated

individual side chains come together upon ligand binding and dimerize

the dimer auto phosphorylates at multiple sites→ activated many proteins → activation of many IC pathways

Tyrosine Kinase Associated Receptors

no intrinsic activity

they are associated with cytoplasmic tyrosine kinases

ligand/receptor binding causes the tyrosine kinase to phosphorylate them since they cant do it themselves

Receptor Serine/threonine Kinases

2 types of receptors activate each other

Type 2 activates and phosphorylates Type 1→ then Type 1 phosphorylates various proteins to relay the signal

end: gene transcription and protein synthesis

Receptor Tyrosine Kinases regulate IC processes such as

Cellular metabolism

Growth and development of cells/tissues

Immunity

Apoptosis

Oncogenesis

Bind hormones as well

Receptor Tyrosine Kinase in hormones:

insulin binding to it leads to phosphorylation of protein that prevents inactivation of GLUT-4 vesicles

in adipose tissue, it prevents the breakdown of triglycerides into free fatty acids bc if they did, it would create ketones → diabetic ketosis

G Protein Couples Receptors

most hormones and many drugs have their effects through G protein linked cascades

aka “7-pass” bc it passes in n out of plasma membrane 7 times

they act indirectly though trimeric, a protein called G-protein

inactive when attached to GDP, so ligand binding site causes to release GDP and bind to GTP= activated protein

What are the 3 subunits that G protein is composed of

alpha, beta, gamma

alpha subunit influences the activity of specific target enzymes and causes G protein to resume its inactive state

target enzyme of G proteins produce…

second messengers that trigger specific IC cascades and alter cell function

G protein types: Gs, Gq, Gi

Gs pathway

aka stimulatory

stimulated Adenylyl cyclase

converts ATP into secondary messenger, cAMP

bind to protein Kinase A which phosphorylates various proteins triggering multiple cellular responses

Examples of ligands that activate G stimulatory pathway

epinephrine- HR, BP, Bronchodilation

Glucagon- promotes release of glucose from liver

Dopamine- regulates mood, motivation, movement

Antidiuretic hormone (ADH)- binds to V2 receptors, results in insertion of aquaporin channels in apical CM= water reabsorption

Gq Pathway “Gq is 2”

Phosphilipase C

forms 2 secondary messengers: IP3, DAG

IP3 travels to smooth ER to release calcium ions= change in cell fxn

DAG remains bound to CM and binds to Protein Kinase C= triggers IC cascades

Gi pathway

inhibitory to the production of cAMP- causes - feedback on Gs

causes alpha subunit to inhibit Adenylate G=Cyclase, leading to decreased lvls of cAMP and subsequent downstream signaling effects

ex: Adenosine, Opioids, Cannabinoids, Somatostatin

cellular comm and cell signaling

to be effective, all receptor systems must be quickly turned off (homeostasis) so that they can respond to the next incoming signal

ex: Beta blockers, NSAIDS, Protein Kinase Inhibitors

Examples of ligands that bind and activate Gq pathway

Acetylcholine - sm contractions, cardiac fxn, neural signals

Angiotensin II- vasoconstriction, aldosterone release, cell growth

Vasopressin (ADH)= regulated vasoconstriction, of vascular sm

Histamine- allergic and inflammatory responses

Thyrotropin-releasing hormone- regulates release of TSH

cell decreases number of activity of receptors when

exposed to excessive concentrations of signaling molecules

receptors can be sent to lysosomes for degradation= down regulation

cells can increase the number of receptors in response to

change in ligand concentration, production of xtra receptors = up regulation

receptors can also be inhibited by

phosphorylation, which blocks them from interacting with their IC targets

proteins that phosphorylate G protein receptors are called GRKs, this turns off signaling cascades which is vital to maintain responsiveness and prevent uncontrolled activity.