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Communication
Communication between cells
• in multicellular organisms cellular functions must be harmonized
• communication can be direct and indirect• direct communication: through gap
junction• 6 connexin = 1 connexon; 2 connexon =
1 pore • diameter 1.5 nm, small organic
molecules (1500 Ms) (IP3, cAMP, peptides) can pass
• called electric synapse in excitable cells (invertebrates, heart muscle, smooth muscle, etc.)
• fast and secure transmission – escape responses: crayfish tail flip, Aplysia ink ejection, etc.
• electrically connected cells have a high stimulus threshold
2/15
Indirect communication• through a chemical substance - signal• signal source - signal - channel - receptor• there are specialized signal sources
(nerve- and gland cells), but many cells do release signals (e.g. white blood cells)
• the chemical character of the signal shows a huge variety:– biogenic amines: catecholamines (NA, Adr,
DA), serotonin (5-HT), histamine, esters (ACh), etc.
– amino acids: glu, asp, thyroxin, GABA, glycine, etc.
– small peptides, proteins: hypothalamic hormones, opioid peptides, etc.
– nucleotides and their derivates: ATP, adenosine, etc.
– steroids: sex hormones, hormones of the adrenal gland, etc.
– other lipophilic substances: prostaglandins, cannabinoids
3/15
Classification by the channel
• this is the most common classification• neurocrine
– signal source: nerve cell– channel: synaptic cleft - 20-40 nm– reaches only the postsynaptic cell (whispering)– the signal is called mediator or
neurotransmitter
• paracrine (autocrine)– signal source: many different types of cells– channel: interstitial (intercellular) space– reaches neighboring cells (talking to a small
company)– the signal sometimes is called tissue hormone
• endocrine– signal source: gland cell, or nerve cell
(neuroendocrine)– channel: blood stream– reaches all cells of the body (radio or TV
broadcast)– the signal is called hormone
4/15
Receptor types• hydrophilic signal – receptor in the cell
membrane• lipophilic signal – receptor in the plasma• the first modifies existing proteins, the
second regulates protein synthesis • the membrane receptor can be internalized
and can have plasma receptor as well (endocytosis)
• membrane receptor types:– ion channel receptors (ligand-gated channels)
on nerve and muscle cells – fast neurotransmission -also called ionotropic receptor
– G-protein associated receptor – this is the most common receptor type - on nerve cells it is called metabotropic receptor – slower effect through effector proteins – uses secondary messengers
– catalytic receptor, e.g. tyrosine kinase – used by growth factors (e.g. insulin) - induces phosphorylation on tyrosine side chains
5/15
Neurocrine communication I.
• Otto Loewi, 1921 - vagusstoff• frog heart + vagal nerve – stimulation
decreases heart rate, solution applied to another heart – same effect – signal: ACh
• neuromuscular junction (endplate), signal: ACh• popular belief: ACh is THE excitatory mediator • in the muscle, it acts through an ionotropic
mixed channel (Na+-K+) – fast, < 1 ms• later: inhibitory transmitters using Cl-
channels• even later: slow transmission (several 100
ms), through G-protein mechanism • neurotransmitter vs. neuromodulator• Dale’s principle: one neuron, one transmitter,
one effect• today: colocalization is possible, same
transmitters are released at each terminal
6/15
Neurocrine communication II.
• good example for the fast synapse: motor endplate, or neuromuscular junction ,
• curare (South-American poison) ACh antagonist• agonists and antagonists are very useful tools• EPSP = excitatory synaptic potential• IPSP = inhibitory synaptic potential• reversal potential – sign changes – which ion is
involved• effect depends also on the gradient – e.g. Cl-
• inhibition by opening of Cl- channel: hyperpolarization or membrane shunt
• presynaptic and postsynaptic inhibition• transmitter release is quantal: Katz (1952) –
miniature EPP, and Ca++ removal + stimulation• size of EPSPs (EPPs) changes in small steps• the unit is the release of one vesicle, ~10.000
ACh molecules• elimination: degradation, reuptake, diffusion
7/15
Integrative functions
• signal transduction is based on graded and all-or-none electrical and chemical signals in the CNS
• neurons integrate the effects • spatial summation - length constant • determines: sign, distance from axon
hillock • temporal summation – time constant • summed potential is forwarded in
frequency code – might result in temporal summation
• release of co-localized transmitters – possibility of complex interactions
8/15
Plasticity in the synapse
• learning and memory is based on neuronal plasticity
• plasticity is needed to learn specific sequence of movements (shaving, playing tennis, etc.)
• formation of habits also depends on plasticity
• it is also needed during development (some connections are eliminated)
• always based on feedback from the postsynaptic cell
• mechanism in adults: modification of synaptic efficacy
9/15
D.O. Hebb’s postulate (1949)
•effectiveness of an excitatory synapse should increase if activity at the synapse is consistently and positively correlated with activity in the postsynaptic neuron
10/15
Types of efficacy changes
• both pre-, and postsynaptic mechanisms can play a role
• few information about postsynaptic changes
• homosynaptic modulation– homosynaptic facilitation: frog muscle –
fast, double stimulus – second EPSP exceeds temporal summation – effect lasts for 100-200 ms
– it is based on Ca++ increase in the presynaptic ending
– posttetanic potentiation – frog muscle stimulated with long stimulus train - depression, then facilitation lasting for several minutes
– mechanism: all vesicles are emptied (depression) then refilled while Ca++ concentration is still high (facilitation)
11/15
Heterosynaptic modulation• transmitter release is influenced by
modulators released from another synapse or from the blood stream
• e.g. serotonin – snails and vertebratesoctopamine - insectsNA and GABA - vertebrates
• presynaptic inhibition belongs here• excitatory modulation
– heterosynaptic facilitation - Aplysia – transmission between sensory and motor neurons increases in the presence of 5-HTmechanism: 5-HT - cAMP - KS-channel closed - AP longer, more Ca++ enters the cell
– long-term potentiation - LTP e.g. hippocampusincrease in efficiency lasting for hours, days, even weeks, following intense stimulationalways involves NMDA receptor
12/15
G-protein associated effect
• called metabotropic receptor in neurons
• always 7 transmembrane regions - 7TM
• it is the most common receptor type
• ligand + receptor = activated receptor
• activated receptor + G-protein = activated G-protein (GDP - GTP swap)
• activated G-protein - -subunit dissociates -subunit – activation of effector proteins -subunit - GTP degradation to GDP –
effect is terminated
13/15
Effector proteins
• Ca++ or K+-channel - opening • action through a second messenger• Sutherland 1970 - Nobel-prize - cAMP
system• further second messengers • modes of action:
– cAMP – IP3 - diacylglycerol – Ca++
• one signal, several modes of action• one mode of action, several possible
signals• importance: signal amplification • effect is determined by the presence
and type of the receptor: e.g. serotonin receptors
14/15
Catalytic receptors
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-20.
15/15
End of text
Gap junction
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 4-33.
Classification by the channel
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 8-1.
Fast and slow neurotransmission
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-12.
The neuromuscular junction
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-13.
The endplate
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-14.
Signal elimination
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-31,34.
Spread of excitation in the CNS
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-1.
AP generation at axon hillock
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-43.
Spatial summation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-44.
Summation of EPSP and IPSP
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-45.
Temporal summation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-46.
Frequency code
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-47.
Neuromodulation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-40,41.
Homosynaptic facilitation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig.6-48.
Ca++-dependency of facilitation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-49.
Posttetanic potentiation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-50.
Heterosynaptic facilitation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-51.
Long-term potentiation
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-52.
Lipid solubility and action
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-8.
Effector proteins: K+-channel
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 6-39.
Second messengers
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-10.
cAMP signalization
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-11.
Inositol triphosphate pathway
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-14.
Ca++ signalization
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-19.
Signal amplification
Alberts et al.: Molecular biology of the cell, Garland Inc., N.Y., London 1989, Fig. 12-33.
Serotonin receptors
Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 1-4.