Communication Communication between cells 215 in multicellular organisms

Communication

Communication between cells 2/15 • 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) (IP 3, c. AMP, 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

Indirect communication 3/15 • through a chemical substance - signal • signal source - signal - channel - receptor • there are specialized signal sources (nerveand 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

Classification by the channel 4/15 • 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

Receptor types 5/15 • 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

Neurocrine communication I. 6/15 • 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

7/15 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

8/15 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

9/15 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

10/15 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

11/15 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)

12/15 Heterosynaptic modulation • transmitter release is influenced by modulators released from another synapse or from the blood stream • e. g. serotonin – snails and vertebrates octopamine - insects NA and GABA - vertebrates • presynaptic inhibition belongs here • excitatory modulation – heterosynaptic facilitation - Aplysia – transmission between sensory and motor neurons increases in the presence of 5 -HT mechanism: 5 -HT - c. AMP - KS-channel closed AP longer, more Ca++ enters the cell – long-term potentiation - LTP e. g. hippocampus increase in efficiency lasting for hours, days, even weeks, following intense stimulation always involves NMDA receptor

G-protein associated effect • called metabotropic receptor in neurons • always 7 transmembrane regions - 7 TM • 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 - c. AMP system • further second messengers • modes of action: – c. AMP – IP 3 - 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

15/15 Catalytic receptors Eckert: Animal Physiology, W. H. Freeman and Co. , N. Y. , 2000, Fig. 9 -20.

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.

c. AMP 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.