Communication. Communication between cells in multicellular organisms cellular functions must be harmonized communication can be direct and indirect direct.

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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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Catalytic receptors

Eckert: Animal Physiology, W.H.Freeman and Co., N.Y.,2000, Fig. 9-20.

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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.