cell communication Flashcards
most common control system (feedback loop) for maintaining homeostasis
negative feedback loop
example of endocrine cell signaling
adrenal medulla releases epinephrine that binds to B1 receptors on heart
example of autocrine cell signaling
NE binding to presynaptic A2 receptor on save nerve terminal that released NE.
neurotransmitter signaling is a specific type of which form of cellular communication?
paracrine signaling
example of a receptor that performs compartmentalization
ryanodine receptor (Ryr) is a scaffolding protein. multiple components of signaling pathways come together on scaffolding proteins to increase their concentrations and effects
calcium channels do this as well
general flow through GPCR
first messenger (ligand) –> receptor –> effector –> second messenger –> cellular response
name 3 chemical messengers derived from arachidonic acid (these are all lipophilic)
prostaglandins
leukotrienes
thromboxanes (eicosanoids. ex: anandamide)
chemical messengers derived from tyrosine (4)
dopamine
NE
epi
iodothyronines
characteristics of steroid chemical messengers
derived from:
where they bind on target cells:
storage:
how they circulate in the blood:
derived from cholesterol
circulate in blood bound to a protein
bind to receptors in cytoplasm or nucleus of target cells
not stored in producing cells
characteristics of eicosanoid chemical messengers
derived from
primarily what kind of actions
how they bind to the cell
storage
precursor
derived from polyunsaturated fatty acids
arachidonic acid is main precursor
primarily autocrine and paracrine actions
unlike steroids, they usually bind to cell surface receptors
not stored in producing cells
which category of signaling molecules are stored in vesicles in the cells that synthesize the molecule (2)
hydrophilic messengers
peptide and protein messengers
opioid peptides include (6)
beta endorphins
dynorphins
enkephalins
substance P
calcitonin gene related peptide (CGRP)
orexins
hydrophilic chemical messengers include (4)
amino acids (glycine, glutamate, gaba, aspartate)
biogenic amines (DA, NE, epi, serotonin, histamine)
choline esters (Ach)
iodothyroxines (T4, T3)
lipophilic chemical messengers include (4, 2 have examples)
steroids (aldosterone, cortisol, testosterone, progesterone, estrogens)
eicosanoids (prostaglandins, leukotrienes, thromboxanes)
VitD, retinoids
how to G proteins turn off
GTPase activity in alpha subunit. catalyzes hydrolysis of GTP to GDP and Pi.
alpha subunit dissociates with effector and goes back to by subunit
what is bound to the alpha subunit of a GPCR when its in the off/inactive state
GDP
what is bound to the alpha subunit of a GPCR when a ligand has attached to the GPCR and it is turned “on” or in the active state
GTP
in the GPCR, what does the GDP GTP exchange do to the aby complex (after activation)
aby complex disassembles into GTP bound alpha subunit and separate by complex
in the activated GPCR, the alpha GTP subunit will interact with effectors that include either
adenylate cyclases (AC)
phospholipase C (PLC)
phospholipase A2 (PLA2)
in the activated GPCR, the by complex subunit will interact with effectors that include either
Gi-0 regulated potassium channels (GIRK)
VgCa2+ channels
B adrenergic receptor kinase (BARK)
heterotrimeric G proteins are classified into 4 families based on nature of alpha subunit (and what they stimulate/inhibit)
Gs (stimulates adenylate cyclase)
Gi, 0 (inhibits adenylate cyclase)
Gq, 11 (activates PLC)
G12, 13 (activates small G proteins)
activated GPCR alpha subunits target these 3 big down stream effectors (and know their second messengers)
adenylyl cyclase (AC) –> cyclic adenosine monophosphatate (cAMP)
phospholipase C (PLC) –> inositol triphosphate (IT3) and diacylglycerol (DAG)
phospholipase A2 (PLC2) –> eicosanoids (20 carbon lipid mediators)
adenylyl cyclase function, inbhibition and stimulation
AC converts ATP to cAMP
Gs stimulates cAMP while Gi inhibits cAMP
PLC function and stimulation
PLC converts PIP2 to IP3 and DAG (both second messengers)
Gq11 with Ca2+ activates PLC
function of IP3
soluble, diffuses into cytoplasm, binds to Ca2+ channels on ER. Ca2+ then is released into cytoplasm from ER
function of DAG
acts as docking site for activator PKC
function of increased cAMP in:
cardiac myocyte
AW and vessel smooth muscle
platelets
principal cell of nephron
cardiac myocyte: increased cAMP increases contractility via b1 receptors
AW and vessel smooth muscle: b2- increased cAMP causes relaxation and dilation
platelets: increased cAMP decreases aggregation (adenosine, P1A2 receptor)
principal cell of nephron: v2- increased cAMP promotes insertion of aquaporin 2 channels in apical membrane
how is the action of cAMP terminated
phosphodiasterases
how is the action of DAG terminated
when the molecule is recycled into new phospholipids
how is the action of IP3 terminated
when the molecule is recycled into new phospholipids
why is free Ca2+ a second messenger
because its an intracellular messenger
which two calcium transporters are found in the plasma membrane
sodium calcium exchanger (NCX)
Ca2+ ATPase (Pump, PMCA)
two types of human synapses in the body
chemical and electrical
Ach synthesis (6 steps)
- glucose enters nerve terminal by passive transport (facilitated diffusion)
- glycolysis converts glucose to pyruvate
- pyruvate is transported into mitochondrion. acetyl group from pyruvate is added to coenzyme A tp produce acetyl co-A which is transported back into the cytoplasm
- choline is actively transported into presynaptic terminal. choline is rate limiting step in Ach synthesis
- choline acetyltransferase (CHAT) catalayzes formation of Ach from acetyl CoA and choline
- Ach is transported into vesicles by H+ anti porter. ach is stored in synaptic vesicles until release
explain Ach elimination
acetylcholinesterase (AchE) in the synaptic cleft hydrolyzes Ach to acetate and choline. choline re enters the nerve terminal and is re used for Ach synthesis
what is required to initiate conformational change for nAchR’s
binding of two Ach’s to the alpha subunits
where are MAchR’s found (4)
CNS, heart, smooth muscle, glands of Gi tract
Gq MAchR’s include
M1, M3, M5
(all have same second messenger pathway)
Gi MAchR’s include
M2, M4
Receptor: NmAchR’s
Signal Transduction:
Locations:
Responses:
Signal Transduction: opening of nonselective cation channels, influx of Na
Locations: skeletal muscle at NMJ
Responses: end plate depol and skeletal muscle contraction
Receptor: NnAchR’s
Signal Transduction:
Locations: (3)
Responses: (5)
Signal Transduction: opening of nonselective cation channels, influx of Na
Locations: autonomic ganglia, adrenal medulla, CNS
Responses: depol of postsynaptic postganglionic neuron, secretion of catecholamines, arousal, attention, analgesia
Receptor: M1
Signal Transduction:
Locations: (2)
Responses: (4)
Signal Transduction: Gq11 –> PLC –> IP3 –> increase in DAG –> increase in Ca2+ –> increase in PKC
Locations: autonomic ganglia, CNS
Responses: excitatory response, arousal, attention, analgesia
Receptor: M2
Signal Transduction:
Locations: (2 specific)
Responses: (3)
Signal Transduction: by subunit of Gi–> increase in K (GIRK) opening
Locations: heart: nodal tissue and cardiac muscle
Responses: slowed spontaneous depolarization (decreased chronotropy, inotropy, dromotropy)
Receptor: M3
Signal Transduction:
Locations: (2)
Responses: (2)
Signal Transduction: Gq11 –> PLC –> increase in IP3 –> increase in DAG –>increase in Ca2+ and PKC
Locations: smooth muscle and Gi
Responses: contraction and increase in salivary secretions
Receptor: M4
Signal Transduction:
Locations: (1)
Responses: (1)
Signal Transduction: Gi, 0 –> inhibits AC –>decrease in cAMP –>
By subunit of Gi–> increase in GIRK (K channel) opening
Locations: CNS
Responses: negative feedback to decrease Ach release
Receptor: M5
Signal Transduction:
Locations: (1)
Responses: (2)
Signal Transduction: Gq11 –> PLC –> IP3 –>increase in DAG –>Ca2+ –> and PKC
Locations: CNS
Responses: promotes dopamine release, dilation of cerebral arteries
primary excitatory neurotransmitter in the brain
glutamate
primary inhibitory neurotransmitter in the brain
GABA
primary inhibitory neurotransmitter in spinal cord and lower brainstem
glycine
in the nerve terminal, glutamine is converted to glutamate via ___________ in the mitochondrial membrane
gutaminase
glutamate release
behaves much like Ach at the nerve terminal. increased intracellular Ca2+ triggers vesicle fusion.
glutamate removal in nerve terminal (1 way, 2 locations)
reuptake of glutamate in nerve terminals occurs via glutamate transporters
glial cells also reuptake glutamate from synaptic cleft via glutamate transporters
3 types of glutamate receptors (that can be inotropic or metabatropic)
- NMDA (n methyl d aspartate)
- alpha amino 3 hydroxy 5 methyl 4 isoxazole propionate receptors (AMPAR)
- kainate receptors.
full activation of NMDA receptors includes binding of what
binding of two glutamates, two glycines, and a depolarizing voltage change.
neuronal injury initiated by excessive glutamate release (excitotoxicity) is the pathologic mechanism in the following diseases (6)
huntingtons
alzeimhers
ALS
stroke and trauma
hyperalgesia
epilepsy
which enzyme catalyzes the decarboxylation of glutamate to GABA
glutamic acid decarboxylase (GAD). amount of GABA correlates to amount of functional GAD
two inhibitory neurotransmitters in nervous system include
GABA and glycine
GABA synthesis
- glutamine enters presynaptic nerve terminal through glutamine transporter
- in mitochondria, glutaminase converts glutamine to glutamate
- back in cytoplasm, GABA is formed by decarboxylation of glutamate. reaction is catalyzed via GAD.
- GABA is transported into vesicles via H+ antiporter then stores in vesicles until release
GABA removal
taken into presynaptic terminal via GABA transporters and repackaged into vesicles aka its recycled. also taken up into glial cells via GABA transporters.
in glia, GABA is converted to glutamate by mitochondrial enzyme, GABA transaminase
this enzyme converts glutamate to glutamine
glutamine synthetase
GABA A receptors (inotropic)
receptor type
activated by
target of (7)
ligand gated Cl- channels
activated by binding of two GABA molecules
target of benzos, barbs, propofol, etomidate, volatiles, neurosteroids, flumazenol
GABA B receptors (metabatropic)
receptor type
activated causes
target of
GPCR
inhibitory effects in post synaptic nephrons via second messenger systems involving
PLC, adenylyl cyclase, By unit opening of K channels and By closing of Ca2+ channels
are glycine receptors inotropic, metabatropic, or both
only inotropic
magnesium ions block this channel at RMP
NMDA
what two binding sites are located in NMDA receptor channel (pore)
Mg2+
ketamine/PCP
NE and epi are metabolized to vanillylmandelic acid by
catechol O methyltransferase (COMT) and monoamine oxidase (MAO)
5 biogenic amine neurotransmitters
- DA
- NE
- Epi
- serotonin (the only inotropic receptor)
- histamine
all catecholamines are synthesized from
tyrosine
tyrosine is hydroxylated to form __________ by the enzyme ____________
L dopa by the enzyme tyrosine hydroxylate. this is the rate limiting step in catecholamine synthesis
what happens to L dopa to yield dopamine
decarboxylated to aromatic L amino acid carboxylase
what enzyme catalyzes the hydroxylation of dopamine to form NE
beta hydroxylase
what enzyme catalyzes the methylation (CH3) of NE to form epi
NE moves out of vescicles back into cytoplasm and phentolamine n methyltransferase (PNMT) catalyzes the methylation of NE to epi
MAO-A preferentially degrades (3)
dopamine
epi
serotonin
MAO-B degradation specs (preference)
degrades dopamine more rapidly than serotonin and NE
end product of catecholamine metabolism
vanillylmandelic acid. (eliminated via urine)
major metabolite of dopamine
homovanillic acid (also ecreted in the urine)
histidine is ________ to form histamine
decarboxylated
what enzymatic reaction is present in ALL biogenic amine neurotransmitter biosynthesis?
decarboxylation
largest concentration of DA neurons in brain is located in
substantia niagra
major concentration of noradrenergic (NE) neurons in CNS is
locus coeruleus in the pons
two major groups of adrenergic (epi) neurons in CNS are
rostral ventrolateral medulla
NTS
serotonin synthesis
metabatropic serotonin receptors and what they activate (3)
5HT1 inhibit adenylyl cyclase
5HT2 stimulate PLC and mobilization of Ca2+
5HT4 stimulate adenylyl cyclase and PKA activation
inotropic serotonin receptor and what it activates
5HT3R- nonselective cation channel. block receptors in area postrema and vagus nerve which normally activates vomiting center
NE preferentially binds to
a1, a2, b1
A1 receptors are coupled with ____ which activates ______ and subsequent downstream reactions
Gq, PLC
A2 receptors are coupled with _______ which inhibits ________ and reduces ________ production
Gi, AC, cAMP
beta adrenergic receptors are coupled to ____ which activates _________ and increases ________ production
Gs, Ac, cAMP
NOS catalyzes the oxidation of _____________ to ____________ and NO (end byproducts)
L arginine (the substrate)
L citrulline
NO is a universal intercellular messenger, acting as both an ___________ and ____________ signaling molecule
autocrine and paracrine
NO synthesis
- glutamate is released from the presynaptic nerve terminal by Ca2+ dependent exocytosis
- glutamate acts on NMDA receptors located on post synaptic neuron, and Ca2+ enters the post synaptic neuron and binds with calmodulin (calcium binding protein)
- Ca2+ calmodulin complex activates NOS
- activation of NOS results in the formation of NO and citrulline from L arginine
- NO interacts with heme moiety of soluble guanylate cyclase resulting in activation of this enzyme
- activated sGC catalyzes conversion of GTP to cGMP in post synaptic neuron. increased levels of cGNMP in post synaptic neuron result in physiologic effect
NO release from post synaptic neurons
- retrograde diffusion of NO into presynaptic terminal is believed to result in enhanced and prolonged NT release from presynaptic neuron (positive feedback)
- NO can also diffuse out to the neighboring neurons. NO stimulates soluble guanylate cyclase and increases cGMP levels
- NO can also diffuse out to adjacent glial cells. in glial cells, NO also stimulates sGC and increases cGMP levels, which then brings about effects
NO termination
highly reactive free radical, having a half life f only a few seconds. cell signaling function of NO are terminated when NO is converted to nitrites* and nitrates* by O2 an H2O
NO is synthesized and released by ____________
endothelial cells
GTP and ATP are classified as
purines
what enzyme converts ATP to adenosine in synaptic cleft
ectonucleotidase
are all neuro peptide receptors inotropic or metabatropic?
metabatropic
insulin and growth factors are endogenous ligands for which receptor
receptor tyrosine kinase (RTK)
leptin and most other cytokines are endogenous ligands for
tyrosine kinase associated receptors
natriuretic peptides are hormone linens for which receptor
guanylyl cyclases
transmembrane catalytic receptors or enzyme linked receptors definition
transduce an extracellular ligand binding interaction into intracellular effect by activating linked enzymatic domain
4 major categories of enzyme linked receptors
- receptor guanylyl cyclases contain systolic domain that catalyzes formation of cGMP from GTP
- receptor tyrosine kinases are largest group of transmembrane catalytic receptors
- tyrosine kinase associated receptors lack inherent catalytic activity. recruit active cystolic signaling proteins in ligand dependent manner
- receptor serine/threonine kinases: have intrinsic catalytic activity. phosphorylate serine and threonine residues on target cytosolic proteins
- receptor tyrosine phosphates: dephosphorylate tyrosine residue on other transmembrane receptors or on cytosolic proteins.
T4 is usually converted to T3 by
deiodinase
in the presynaptic nerve terminal, opioid activated GPCR gy subunits block
VgCa channels
B1 receptor helps cardiac performance in at least 4 ways
inotropy
chronotropy
lucitropy (relaxation)
dromotropy (conduction velocity)
how does B1 receptor activation in SA and AV node lead to positive chronotropy and dromotropy
phosphorylation of L type Ca2+ channels and phospholamban lead to increased intracellular Ca2+ which leads to increased rate of phase 4 depolarization. (positive chronotropy)
same pathway enhances excitability and firing and thus dromotropy
NO mediated vascular smooth muscle relaxation (7 steps)
- stress, Ach, histamine, bradykinin, 5HT, substance P, ATP increase intracellular Ca2+.
- Ca2+ comines with calmodulin (CaM) and the Ca/CaM complex activates endothelial NOS (eNOS)
- eNOS produces NO from L arginine. NO diffuses to VSMC’s
- NO in smooth muscle cells activate soluble guanylyl cyclase (sGC), which catalyzes conversion of GTP to cGMP
- cGMP activates downstream effects promoting smooth muscle relaxation and vasodilation
- NO also activates K channels leading to increased K efflux and hyperpolarization of cell membrane,.
- net effect is relaxation of smooth muscle cell
3 drugs that donate NO directly to VSMC’s
NGT, Na nitroprusside, isosorbide dinitrate
presynaptic inhibitory response of opioids
GBy subunits block VgCa channels. decreased Ca2+ influx in presynaptic terminal leads to reduced NT release and suppression of synaptic communication
postsynaptic inhibitory response to opioids
inhibition of adenylyl cyclase and cAMP production and PKA activation resulting in modulation of VgNa channels.
activate inwardly rectifying K channels (GIRK) leading to hyperpolarization of post synaptic membrane.
activate protein kinase cascades and DNA transcription
taken together, the post synaptic responses to opioids are decreased excitability and potential long term tolerance to opioids
vasopressin has two other names
arginine vasopressin (AVP) and of course ADH
vasopressin signaling at the nephron
vasopressin binds to V2 GPCR’s on basolateral membrane activating Gs protein
Gs stimulates adenylyl cyclase to produce cAMP.
cAMP activates PKA
PKA phosphorylates H2O channel aquaporin 2 (AQP2) and activates transport and fusion of aquaporin containing vesicles in apical membrane
increased APQ2 in apical membrane increases water reabsorption
regulation of water reabsorption in collecting duct modulates urine and plasma osmolality and intravascular volume
PDE3 binds to
and is found in (3)
binds to cAMP and cGMP but has 10x the affinity for cAMP
- found in heart, VSMC, and placental smooth muscle and tissues important in energy homeostasis (liver, pancreatic beta cells, adipocytes)
2 drugs that are selective PDE3 inhibitors
milrinone and amrinone
what happens when PDE3 is inhibited
increases cAMP levels and prolongs downstream signaling effects.
in heart: promotes positive chronotropy, dromotropy, inotropy, lusitropy
in VSMC, increased cAmP leads to vasodilation
milrinone is used to tx (3)
pHTN, cerebral vasospasm after aneurysmal SAH, neonatal septic shock
PDE5 binds to
is found in (3)
cGMP selective
found in tissue throughout the body with higher levels in corpus cavernous (erectile tissue of peepee and clitoris), VSMC’s, and platelets
medications that are PDE5 inhibitors (3) and what they’re used to tx (4)
“afil”
sildenafil, vardenafil, tadalafil
tx: ED, pHTN, high altitude sickness, memory dysfunction
PDE5 inhibitors are metabolized by
CYP450 3A4 in the liver
PDE4 binds to
and is found in
caMP selective
modulates B2 adrenergic responses in pulmonary smooth muscle
PDE4 drug used for COPD and metabolism of drug
roflumilast
undergoes extensive hepatic metabolism by both phase 1 and 2 reactions
