Ch.12, Part 2 - Channels & Electrical Properties of Membranes

Question 1

T/F: Transporters are typ more efficient than ion channels.

Answer 1

False

Ion channels are more efficient that xprtrs: can pass up to 100 mil ions/sec (per channel); 10⁵ x faster than any known xprtr.

Question 2

Channel transport is always ______ (up/downhill) and typ involves transport of the following four ions: __, __, __, __.

Answer 2

Channel transport is always downhill (can’t be coupled to energy source for active/uphill xprt) and typ involves transport of the following four ions: Na+, K+, Ca2+, and Cl-.

Question 3

Aquaporins are permeable to ______ and impermeable to _____.

Answer 3

Aquaporins are permeable to water and impermeable to ions.

Question 4

Solutes both inside and outside the cell contribute to the net osmotic gradient. Describe ea of these forces as well as the net direction of water flow until balancing via turgor/osmotic pressure.

Answer 4

• Fixed anions - neg charged organic molecules confined inside cell
• IC Cations - balance out charge of fixed anions.
• Osmotic grad created by fixed anions/IC cations is balanced by an opp osmotic grad due to high concen of EC inorganic ions (Na+ and Cl–).
• Resultant small osmotic force tends to “pull” water into cell → cell swells until osmotic pressure balances.

Question 5

Despite a net osmotic gradient pulling water into the cell, most animal cells don’t display a large change in volume. Why?

Answer 5

Cytoplasm in most animal cells is gel-like → resists large changes in volume in response to changes in osmolarity.

Question 6

All bio mems are moderately permeable to water. Beyond simply increasing the rate of water transport, what makes aquaporins so imp?

Answer 6

Aquaporins provide signif more rapid xprt of water while completely blocking ions → avoids disrupting ion grads.

• partic abundant in cells wh req rapid xprt of nutrients/water, e.g. epithelial cells of kidney or exocrine cells.

Question 7

Aquaporins form narrow pores lined w hphilic AAs on one side and hphobic AAs on other. What specific AA(s)/side chains contrib to the hphilic side, and what effect does this have on how water molecules traverse thru the channel?

Answer 7

Aquaporins form narrow pores lined w hphilic AAs on one side and hphobic AAs on other.:

• Hphilic AAs incl two asparagines (Asn; N) and other AAs w carbonyl (C=O) side chains.
• Water molecules traverse mem in single file → follow path of carbonyl oxygens.
• Both physically too narrow and energ unfav for any hydrated ion to enter.

Question 8

Aquaporins form narrow pores lined w hphilic AAs (Asn and other AAs w carbonyl side chains) on one side and hphobic AAs on other, resulting in water traversing the mem in single file, following the path of carbonyl oxygens. Why can’t hydrated ions also pass in single file?

Answer 8

Both physically too narrow and energ unfav for any hydrated ion to enter, e.g. K+, Na+, Ca2+, or Cl– ions; nor H+.

• The two strategically placed Asn’s bind O of central water molecule in the line of water molecules traversing pore, making both valences of central O unavailable for H-bonding and imposing a bipolarity on entire column of water molecules
  
  • Impossible to rapidly make/break H-bonds → H+ cannot diffuse thru pore.
  • Recall: H+ (as H3O+) typ diffuses thru water v rapidly.
• Peptide bonds have an electric dipole: partial neg charge on O of C=O (C-terminal) and partial pos charge on N of N-H (N-terminal) → in alpha helix, H-bonds align dipoles, and thus every alpha helix has a net electric dipole along its axis → facilitates single-file traversing of water.

Question 9

Wh two imp props distinguish ion channels fr aquaporins?

Answer 9

Ion channels are gated and show ion selectivity (selectivity filter).

Question 10

Describe how ion channels show ion selectivity (selectivity filter).

Answer 10

Ion channels show ion selectivity (selectivity filter):

• Pores must be narrow enough in places to force ions into close contact w walls of channel → only approp sized/charged ions can pass.
• Permeating ions must shed most/all of assoc water to pass thru narrowest part of channel (selectivity filter) → limits rate of passage.
• As ion concen ↑ → flux of ion thru channel ↑ proportionally, then levels off (saturates) at a max rate.

Question 11

As ion concen ↑, how does flux thru an ion channel change?

Answer 11

As ion concen ↑ → flux of ion thru channel ↑ proportionally, then levels off (saturates) at a max rate.

Question 12

Ion channels are gated: w prolonged stim (chem/elec), most ion channels go into _____ (open/closed) state → refractory until stim removed.

Answer 12

Ion channels are gated: w prolonged stim (chem/elec), most ion channels go into closed (desensitized/inactivated) state → refractory until stim removed.

Question 13

What are the three most common types of gated ion channels?

Answer 13

Voltage, mechanical, and ligand-gated ion channels are the most common.

• Ligand can be either an EC mediator (e.g. nxmtr-gated) or an IC mediator, e.g. ion-/ntide-gated channels.
• Protein de/phosphorylation also regulates activity of many ion channels.

Question 14

_______ channels are a subset of K+ channels wh open even in unstim/resting state.

Answer 14

K+ leak channels are a subset of K+ channels wh open even in unstim/resting state → make pmem much more permeable to K+ than other ions → critical role in maintain Vr.

• There are leak channels for Na+ and other ions, but K+ leak channels are much more abundant → more signif role in maintaing Vr.
• Recall: Vr is typ neg: Na/K pumps (antiporters) transport 3 Na+ out and 2 K+ in w ea ATP hydrolyzed → establishes a cgrad for both K+ and Na+ → K+ freely leak out and Na+ leak in much more slowly → established an egrad (neg inside) → rate of K+ leaking out ↓ and Na+ leaking in ↑ → K+ and Na+ reach an equilibrium state according to their respective echem grads → net Vr is neg.

Question 15

Mem potential in animal cells deps mainly on ______ channels and the ___ gradient across the pmem.

Answer 15

Mem potential in animal cells deps mainly on K+ leak channels and the K+ echem gradient across the pmem.

• Recall: Na+ leak channels also present, but much less abundant.
• echem equilibrium results in negative Vr.

Question 16

T/F: Mem pot (charge diff across mem) can result both fr active pumping and passive ion diffusion.

Answer 16

True

Mem pot (charge diff across mem) can result both fr active pumping (e.g. Na/K pumps) and passive ion diffusion (e.g. K+ leak channels).

• Animals: mem-pot across pmem deps mainly on passive ion movements.
• Electrogenic H+ pumps in inner mito mem generate most of mem-pot across this mem.
• Electrogenic pumps also generate most of mem-pot across pmem in plants/fungi.

Question 17

K+ leak channels are primarily responsible for the resting mem potential (Vr). What, then, is the purpose of Na/K pumps, and what effect do they have on Vr?

Answer 17

Recall: Na/K pump - P-type ATPase; an ATP-driven antiporter that pumps 3 Na+ out and 2 K+ in for ea ATP hydrolyzed, i.e. active xprt (not passive like K+ leak channels).

• Vr is typ neg: Na/K pumps establish a cgrad for both K+ and Na+ → K+ freely leak out and Na+ leak in much more slowly → establishes an egrad (neg inside) → rate of K+ leaking out ↓ and Na+ leaking in ↑ → K+ and Na+ reach an equilibrium state according to their respective echem grads → net Vr is neg
• Na/K pumps set up and maintain the necessary ion grads (partic Na+, also K+) wh drives xprt of most nutrients into animal cells, as well as play a crucial role in regulating cytosolic pH.
  
  • Hence, Na/K pumps indirectly establish Vr thru secondary active xprt.

Question 18

Which equation is used to quantify equilibrium conditions across mem?

Answer 18

Nernst equation - quantifies equil condition → calc theoretical Vr if we know ratio of IC/EC ion concens.

• Pmem of a real cell is not exclusively permeable to K+/Cl– → actual Vr typ not exactly equal to that predicted by Nernst equation for K+/Cl–.

Question 19

T/F: a signif amount of inorganic ions must cross the pmem to set up a mem potential.

Answer 19

False

Only minute # of inorganic ions must cross pmem thru to set up mem-pot, i.e. ion concens virtually unchanged.

Question 20

Describe what might happen upon the sudden inactivation of Na/K pumps.

Answer 20

Sudden inactivation of Na/K pump → slight drop in mem-pot (less neg) occurs immediately, but K+ equilibrium mechanism—wh generates majority of mem-pot—persists.

• As long as IC [Na+] stays low & IC [K+] stays high → K+ equil mechanism persists → maintains mem-pot for many minutes.
  
  • I.e. the echem grad for K+ remains relatively balanced: K+ effuses thru leak channels (along cgrad), but still resisted by its egrad (neg Vr).
• After some time, K+ AND other ion leak channels (e.g. Na+ leaking in) result in a slight depolarization (less neg Vr).

Question 21

Bacterial K+ channels are composed of ___ (2/4/6) _____ (identical/diff) xmem subunits wh form a central pore. Ea subunit contribs ____ (2/4/6) α helices, wh form a cone w its wide end facing the ___ (IC/EC space) where K+ ions _____ (enter/exit) fr the channel. A short α helix called the _______ connects the xmem helices and forms a crucial “selectivity loop” that acts as a __________. The selectivity loops are lined by _______ of polypeptide backbones (peptide bonds).

Answer 21

Bacterial K+ channels are composed of 4 identical xmem subunits wh form a central pore. Ea subunit contribs 2 α helices, wh form a cone w its wide end facing the EC space where K+ ions exit fr the channel. A short α helix called the pore helix connects the xmem helices and forms a crucial “selectivity loop” that acts as a selectivity filter. The selectivity loops are lined by carbonyl oxygens of polypeptide backbones (peptide bonds).

Question 22

The selectivity filter of bacterial K+ channels is formed by “selectivity loops” lined by carbonyl oxygens of polypeptide backbones (peptide bonds). Explain how these carbonyl oxygens select for ions.

Answer 22

Selectivity filter of bacterial K+ channels:

• Carbonyl oxygens are rigidly spaced at exact distance to accommodate selected ion.
  
  • E.g. Na+ cannot enter K+ channel bc carbonyl O’s are too far away apart to compensate for energy expense assoc w loss of water molecules req’d for entry.
  • Recall: Na+ has smaller atomic size.

Question 23

Describe the gating mechanism shared by many ion channels.

Answer 23

Dep on partic type of channel, helices tilt, rotate, or bend during gating → either obstruct/open path for ion xprt.

• Gating helices typ allosterically coupled to domains that form ion-conducting pathway → conform change in gate (e.g. in response to ligand binding) → conform change in conducting pathway (opens/closes).
• E.g. closed K+ channel → inner helices tilt → pore constricts like a diaphragm at its cytosolic end → bulky hphobic AA side chains block small opening remains and prevents entry of ions.

Question 24

All orgs must sense/respond to int/ext mech forces (e.g. sound, touch, pressure, shear forces, and gravity, or osmotic pressure and mem bending), yet channels directly linked to mechanical gating are v rare. How, then, do cells respond to mech forces?

Answer 24

Mechanosensitive channels - v rare; few directly linked to mech gating.

• E.g. auditory hair cells in human cochlea: contain v sensitive mech-gated ion channels, but ea of ~15,000 individual hair cells is thought to have total of only ~50–100.

Cells have several diff channels that open at diff levels of pressure:

• Mechanosensitive channel of small conductance—the MscS channel—opens at low/mod pressures.
  
  • Composed of seven identical subunits; in open state, form pore ~1.3 nm in diam—just big enough to pass ions/small molecules.
  • Large cytoplasmic domains limit size of molecules that can reach pore.
• Mechanosensitive channel of large conductance—the MscL channel—opens at high/v high pressure to 3+ nm; last resort.

Question 25

Wh part of a neuron houses the nucleus and is the point of convergence for axons/dendrites that radiate outward?

Answer 25

**Cell body** - houses nucleus; thin processes (axons/dendrites) radiate outward.

Question 26

Neurons typ contain one long axon that conducts signals _____ (toward/away fr) cell body.

Answer 26

Neurons typ contain one long axon that conducts signals **away fr** cell body → toward distant targets. * Axons typ divide at far end into many branches → pass signal to many target cells simult.

Question 27

T/F: Neurons are composed of a cell body, wh houses the nucleus, and thin processes (axons/dendrites) that radiate outward. Only the axons and dendrites are involved in receiving/transmiting signals, not the cell body.

Answer 27

False The cell body can receive signals.

Question 28

Neural signals always take the same form of changes in electrical potential across the neuron's pmem. How do short- and long-distance signals differ?

Answer 28

Signal spreads; unless neuron expends energy to amplify it, signal weakens w ↑ distance fr source. * **Short-distance**: attenuation is unimp; many small neurons conduct signals *passively* (w/o amp). * **Long-distance**: passive spread is inadequate → larger neurons employ an *active* signaling mechanism.

Question 29

\_\_\_\_\_\_\_\_\_\_\_ are an elec stim that exceeds threshold → triggers explosion of elec activity → propagates _______ (slowly/rapidly) along neuron’s pmem, and sustained by automatic \_\_\_\_\_\_\_\_.

Answer 29

**Action potentials (APs; nerve impulses)** are an elec stim that exceeds threshold → triggers explosion of elec activity → propagates **rapidly** along neuron’s pmem, and sustained by automatic **amplification**.

Question 30

APs are a direct result of \_\_-gated ______ (cation/anion) channels.

Answer 30

APs are a direct result of **V**-gated **cation** channels. * Pmem of *all* elec-excitable cells—incl neurons, muscle, endocrine, egg cells—contain v-gated cation channels → resp for generating APs.

Question 31

APs are triggered by a depol of the pmem. Describe this process in a local mem region, i.e. not spreading.

Answer 31

**AP is triggered by depol of pmem - in nerve/skeletal muscle cells, stim that causes sufficient depol...:** * **promptly opens v-gated Na+ *channels*** → small, *passive* influx of Na+ → influx of pos charge depols mem further → opens more Na+ channels → ...(**self-amplification**). * Self-amp continues until e-pot in *local* region of mem has shifted fr Vr (~**–40 mV** in humans) to almost as far as Na+ equil pot (~**+50 mV**) → **net Na+ echem grad plummets to nearly zero**. * Near-zero Na+ echem grad causes **Na+ channels to inactivate** → **v-gated K+ channels open** → **restore Vr**. Note: these v-gated channels are not the same as the leak channels that establish Vr in normal conditions.

Question 32

V-gated Na+ channels are composed of __ (1/2/4) polypeptide chain(s) w ___ (2/4/6) structurally v similar domains. Ea domain contributes to a central channel (similar to K+ channels) and contains a voltage sensor, characterized by an unusual xmem helix (S4) that contains many _____ (pos/neg) charged AAs. As the local pmem depols, S4 helices experience an e-static pulling force that attracts them to the now ___ (neg/pos) charged EC side of the pmem → conform change _____ (opens/closes) the channel.

Answer 32

V-gated Na+ channels are composed of **one** polypeptide chain w **4** structurally v similar domains. Ea domain contributes to a central channel (similar to K+ channels) and contains a voltage sensor, characterized by an unusual xmem helix (S4) that contains many **pos** charged AAs. As the local pmem depols, S4 helices experience an e-static pulling force that attracts them to the now **neg** charged EC side of the pmem → conform change **opens** the channel.

Question 33

T/F: V-gated Na+ channels reclose rapidly even though mem is still depolarized.

Answer 33

True ## Footnote V-gated Na+ channels reclose rapidly even though mem is still depolarized.

Question 34

What is meant by the refractory period of v-gated Na+ channels? What is its purpose?

Answer 34

**Refractory period** - time req'd for sufficient # of Na+ channels to recover fr inactivation and support new AP; limits repetitive firing rate of neuron. * Channels reclose rapidly even though mem is still depol'd → remain in inactivated state, unable to reopen, until after Vr restored. * Na+ channel can exist in three distinct states: closed, open, and inactivated.

Question 35

V-gated Na+ channels can exist in three distinct states: closed, open, and inactivated. Describe when ea of these states are present.

Answer 35

Na+ channel can exist in three distinct states **dep on wh has the lowest free energy (most stable)**: closed, open, and inactivated: * **Closed** - lowest energy (most stable) when mem highly polarized (e.g. **Vr**). * **Open** - lower energy than closed state but higher than inactivated state when mem depolarized (e.g. AP) → "**metastable**", i.e. channel remains in this state for a **randomly variable period of time**, then becomes inactivated (lowest energy when mem depols). * **Inactivated** - lowest energy (most stable) when mem depolarized (e.g. **after AP; refractory period**).

Question 36

\_\_\_\_\_\_\_\_\_\_ occurs when the self-amplifying depolarization of a localized patch is sufficient to depol neighboring regions.

Answer 36

**Spreading activation** occurs when the self-amplifying depolarization of a localized patch is sufficient to depol neighboring regions → go thru same depol/AP gen cycle.

Question 37

\_\_\_\_\_\_\_\_\_\_ are photosensitive ion channels that open in response to light.

Answer 37

**channel rhodopsins** are photosensitive ion channels that open in response to light. * Struc closely resembles b.rhodopsin: * Covalently bound retinal group that absorbs light → isomerization rxn → triggers conform change in protein → opens ion channel in pmem. * In contrast to b.rhod, wh is light-driven proton pump, c.rhod is light-driven cation channel.

Question 38

Myelination ___ (↑/↓) the _____ and ______ of AP propagation in nerve cells.

Answer 38

Myelination **↑** the **speed** and **efficiency** of AP propagation in nerve cells. * **Myelin sheath** insulates axons of many vertebrate neurons → greatly ↑ rate of AP gen.

Question 39

Glial cells are specialized non-neuronal supporting cells. What function do they serve?

Answer 39

**Glial cells** - specialized non-neuronal supporting cells; **synth myelin** and wrap their pmem into tight spiral around axons → **insulate axonal mem (↓ current leak**). * **Schwann cells** - glial cells that myelinate axons in PNS. * **Oligodendrocytes** - glial cells that myelinate axons in CNS.

Question 40

Glial cells are specialized non-neuronal supporting cells that synth myelin and wrap their pmem into tight spiral around axons → insulate axonal mem (↓ current leak). What are the two types of glial cells?

Answer 40

* **Schwann cells** - glial cells that myelinate axons in PNS. * **Oligodendrocytes** - glial cells that myelinate axons in CNS.

Question 41

Almost all v-gated Na+ channels are located in the regularly spaced interruptions in myelin sheath covering the axon, called \_\_\_\_\_\_\_\_\_\_.

Answer 41

Almost all v-gated Na+ channels are located in the regularly spaced interruptions in myelin sheath covering the axon, called **Nodes of Randvier**.

Question 42

Nodes of Ranvier are regularly spaced interruptions in myelin sheath and the location of almost all Na+ channels in the axon. These nodes enable _______ conduction, wh allows the AP to propagate along the myelinated axon by jumping fr node to node.

Answer 42

Nodes of Ranvier are regularly spaced interruptions in myelin sheath and the location of almost all Na+ channels in the axon. These nodes enable **saltatory** conduction, wh allows the AP to propagate along the myelinated axon by jumping fr node to node. * Two main advantages: APs travel v much faster, and metabolic energy conserved.

Question 43

T/F: Ion channels open in all-or-nothing fashion.

Answer 43

True Ion channels open in all-or-nothing fashion.

Question 44

Neurons are theorized to be "self-tuning" devices. What is meant by this?

Answer 44

Individual neurons are self-tuning devices, i.e. constantly adjust expression of ion channels and nxmtr receptors. * Homeostatic control: as conditions change, neuron can modify #s of depolarizing (Na+ and Ca2+) and hyperpolarizing (K+) channels.

Question 45

\_\_\_\_-gated ion channels convert chem signals into electrical ones at chemical \_\_\_\_\_\_\_\_.

Answer 45

**Transmitter**-gated ion channels convert chem signals into electrical ones at chemical **synapses**.

Question 46

\_\_\_\_\_\_\_ are specialized sites whr neuronal signals are transmitted fr cell to cell (typ indirectly) and the ________ is the narrow space isolating cells fr one/an.

Answer 46

**Synapses** are specialized sites whr neuronal signals are transmitted fr cell to cell (typ indirectly) and the **synaptic cleft** is the narrow space isolating cells fr one/an.

Question 47

Chemical synapse: AP arrives at presynaptic site → depol of mem opens v-gated ____ channels (clustered in presyn mem) → influx triggers release of nxmtrs (stored in \_\_\_\_\_\_\_\_\_\_) into cleft via exocytosis → xmtr diffuses _______ (slowly/rapidly) across synaptic cleft → provokes elec change in postsynaptic cell by binding/opening \_\_\_\_-gated ion channels.

Answer 47

Chemical synapse: AP arrives at presynaptic site → depol of mem opens v-gated **Ca2+** channels (clustered in presyn mem) → influx triggers release of nxmtrs (stored in **mem-enclosed vesicles**) into cleft via exocytosis → xmtr diffuses **rapidly** across synaptic cleft → provokes elec change in postsynaptic cell by binding/opening **xmtr**-gated ion channels.

Question 48

Briefly describe how chemical synapses work.

Answer 48

Chemical synapse: AP arrives at presynaptic site → depol of mem opens v-gated Ca2+ channels (clustered in presyn mem) → influx triggers release of nxmtrs (stored in mem-enclosed vesicles) into cleft via exocytosis → xmtr diffuses rapidly across synaptic cleft → provokes elec change in postsynaptic cell by binding/opening xmtr-gated ion channels.

Question 49

What happens to nxmtrs released into the synaptic cleft?

Answer 49

Nxmtrs are **rapidly destroyed** by enzymes in synaptic cleft or **taken back up** by presyn nerve terminal or surrounding glial cells. * Reuptake is mediated by variety of Na+-dep nxmtr symporters. * Nxmtrs are recycled → allow cells to keep up w high rates of release. * Rapid removal → ↓ interaction w neighboring neurons; clears synaptic cleft before next pulse of nxmtr released → *timing* of repeated, rapid signals can be accurately communicated to postsynaptic cell.

Question 50

Why is the rapid removal (via degradation or reuptake) imp in nerve signalling?

Answer 50

Nxmtrs are rapidly destroyed by enzymes in synaptic cleft or taken back up by presyn nerve terminal or surrounding glial cells. * Reuptake is mediated by variety of Na+-dep nxmtr symporters. * Nxmtrs are recycled → allow cells to keep up w high rates of release. * Rapid removal → ↓ interaction w neighboring neurons; clears synaptic cleft before next pulse of nxmtr released → **timing of repeated, rapid signals can be accurately communicated to postsynaptic cell**.

Question 51

Xmtr-gated ion channels, also called ________ receptors, rapidly convert _______ signals into elec signals at chem synapses.

Answer 51

Xmtr-gated ion channels, also called **ionotropic** receptors, rapidly convert **EC chem** signals into elec signals at chem synapses. * Concentrated in specialized region of postsyn pmem; open *transiently* in response to binding of nxmtrs → produce *brief* permeability change in mem.

Question 52

Xmtr-gated ion channels (ionotropic receptors) rapidly convert EC chem signals into elec signals at chem synapses. However, these channels cannot directly produce self-amplifying excitation. Why?

Answer 52

Xmtr-gated ion channels (ionotropic receptors) rapidly convert EC chem signals into elec signals at chem synapses. * **Relatively insensitive to mem-pot** (unlike v-gated channels) → cannot directly produce self-amplifying excitation; * Instead, produce *local* permeability change → *indirectly* changes mem-pot. * Degree of excitation is graded according to amount of nxmtr released and how long it persists. If summation of small depols opens sufficient #s of nearby v-gated cation channels → AP triggered. * May req opening of xmtr-gated ion channels at *numerous* synapses in close proximity.

Question 53

T/F: xmtr-gated ion channels can act as either receptors or channels.

Answer 53

True Xmtr-gated ion channels can act as either recepotrs or channels. * As receptors: highly selective nxmtr binding sites. * As channels: selective type of ions xprtd.

Question 54

Chem synapses/nxmtrs can be excitatory or inhibitory. Describe the diffs b/w these.

Answer 54

* **Excitatory nxmtrs** - open cation channels → influx of Na+ or Ca2+ → depols postsyn mem toward threshold for firing AP. * Typ incl acetylcholine (ACh), glutamate, serotonin. * Glutamate mediates most of excitatory signaling in vertebrate brain. * **Inhibitory nxmtrs** - open either Cl– or K+ channels → suppresses AP firing by opposing depol of postsyn mem. * Typ incl γ-aminobutyric acid (GABA) and glycine. * **Many xmtrs can be either excitatory/inhibitory, dep on whr released, wh receptors they bind, and ionic conditions encountered**. * E.g. ACh: excites/inhibits dep on type of ACh receptors it binds; recall: typ excitatory.

Question 55

Many xmtrs can be *either* excitatory/inhibitory. What dets the nature of their action?

Answer 55

* Many xmtrs can be *either* excitatory/inhibitory, **dep on whr released, wh receptors they bind, and ionic conditions encountered**. * E.g. ACh: excites/inhibits dep on type of ACh receptors it binds; recall: typ * **Excitatory nxmtrs** - open cation channels → influx of Na+ or Ca2+ → depols postsyn mem toward threshold for firing AP. * Typ incl acetylcholine (ACh), glutamate, serotonin. * Glutamate mediates most of excitatory signaling in vertebrate brain. * **Inhibitory nxmtrs** - open either Cl– or K+ channels → suppresses AP firing by opposing depol of postsyn mem. * Typ incl γ-aminobutyric acid (GABA) and glycine.

Question 56

Opening K+ channels tends to keep cell close to equil pot for K+, wh is typ close to Vr bc, at rest, K+ channels are the main type of channel open; when additional K+ channels open → harder to drive cell away fr resting state, i.e. inhibits gen of AP. Describe how Cl- gated channels exhibit a similar effect.

Answer 56

**Cl^--gated channels**: * **IC [Cl–] \<\< EC**, but **Vr opposes influx**. * For many neurons, equil pot for Cl– is close to Vr (or even more neg): mem starts to depol (less neg) → Cl– channels open → neg charged Cl– ions enter cell → counteracts depol; i.e. **inhibitory**.

Question 57

Not all chem signaling in nervous sys operates thru ionotropic ligand-gated ion channels. What other class of receptors contributes to chem signalling?

Answer 57

**Most nxmtrs secreted by nerve terminals**—incl large variety of neuropeptides—**bind to metabotropic receptors**, wh regulate ion channels only indirectly thru small IC signal molecules. **Two major classes of receptors**—**ionotropic** or **metabotropic**—based on signaling mechanisms: * **Ionotropic receptors** - ion channels; used in fast chem synapses. * ACh/glutamate and glycine/GABA all act on xmtr-gated ion channels → mediate signaling that is typ immediate, simple, and brief. * **Metabotropic receptors** - **G-protein-coupled receptors**. * Bind all other nxmtrs; can also bind ACh, glutamate, and GABA. * Signaling typ far slower and more complex; effects also longer-lasting.

Question 58

Most psychoactive drugs affect synaptic signaling by binding to ________ receptors.

Answer 58

Most psychoactive drugs affect synaptic signaling by binding to **nxmtr** receptors. * Anesthetics such as plant-derived curare block ACh receptors on skeletal muscle cells. * Most drugs used to treat insomnia, anxiety, depression, and schizophrenia exert effects at chem synapses, many wh bind xmtr-gated channels. * Barbiturates, tranquilizers (Valium), and sleeping pills (Ambien) bind GABA receptors → ↓ GABA concen req'd to open Cl- channels → amplifies inhibitory action of GABA. Other components of synaptic signaling machinery are also potential targets for psychoactive drugs. * Recall: nxmtrs are cleared by reuptake mechanisms mediated by Na+-driven symports. * Antidepressants (Prozac) **inhibit reuptake** of serotonin → prolong effect → strengthen synaptic transmission. * Other psychoactive drugs inhibit reuptake of both serotonin and norepinephrine.

Question 59

Describe the mechanism of nerve impulses stimulating muscle cells to contract.

Answer 59

**Mechanism of nerve impulse stimulating muscle cell to contract**: reqs sequential activation of at least five diff sets of ion channels, all w/i few milliseconds. * Nerve impulse reaches nerve terminal → depols pmem of terminal → *transiently* opens v-gated **Ca2+ channels** in presyn mem → Ca2+ flows into nerve terminal → ↑ IC [Ca2+] triggers *local* release of **ACh** via exocytosis into synaptic cleft. * **ACh binds ACh receptors** in muscle cell pmem → *transiently* opens cation channels → influx of **Na+** → *local* mem depols. * Local depol opens v-gated **Na+ channels** → **self-amp/self-propagating** depol (AP; spreading activation). * Generalized depol of muscle cell pmem → activates v-gated **Ca2+ channels in transverse tubules** (T tubules). * V-gated Ca2+ channels open → **Ca2+-release channels**—in adj region of SR mem—open transiently → release Ca2+ stored in SR into cytosol → sudden ↑ in cytosolic [Ca2+] → **myofibrils in muscle cell contract**. * T-tubule/SR mems are closely apposed; joined t/g in specialized struc: activation of v-gated Ca2+ channel in T-tubule pmem → channel conform change → mechanically transmitted to Ca2+-release channel in SR mem (opens) → Ca2+ flows fr SR lumen into cytoplasm.

Question 60

Motor neurons can be excitatory or inhibitory. Nxmtrs released at excitatory synapses result in a small _____ (depol/hyperpol) in postsyn mem, also called a(n) \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_. Nxmtrs released at inhibitory synapses result in a small _____ (depol/hyperpol) in postsyn mem, also called a(n) \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.

Answer 60

Motor neurons can be excitatory or inhibitory. Nxmtrs released at excitatory synapses result in a small **depol** in postsyn mem, also called a(n) **excitatory postynaptic potential (excitatory PSP)**. Nxmtrs released at inhibitory synapses result in a small **hyperpol** in postsyn mem, also called a(n) **inhibitory postsynaptic potential (inhibitory PSP)**.

Question 61

The pmem of dendrites/cell body of most neurons contains relatively low density of v-gated Na+ channels (most abundant at nodes/axon hillock) → individual excitatory PSPs are typ too small to trigger AP. How does this affect short and long-distance transmission?

Answer 61

* Ea incoming signal initiates *local* PSP → **degrades w distance fr site of synapse**. * If signals arrive *simult* at several synapses in same region of dendritic tree → **total PSP in general region is roughly the sum of individual PSPs; inhibitory PSPs subtract fr total**. * PSPs fr ea general region spread passively → converge on cell body. * **Long-distance transmission**: combined magnitude of PSP is translated (encoded) into freq of AP firing. * **As magnitude of stim/depol ↑ → freq of APs ↑**.

Question 62

As magnitude of stim/depol ↑ → ____ of APs ↑.

Answer 62

As magnitude of stim/depol ↑ → **frequency** of APs ↑.

Question 63

The ___________ is a specialized region of the axonal mem at junction of axon/cell body; rich in v-gated ____ channels as well as three classes of ___ channels and one class of ____ channel.

Answer 63

The **initial segment (axon hillock)** is a specialized region of the axonal mem at junction of axon/cell body; rich in v-gated **Na+** channels as well as three classes of **K+** channels and one class of **Ca2+** channel. * Initial segment is resp for **encoding** signals. * **K+ channels**: delayed, rapidly inactivating, and Ca2+-activated K+ channels.

Question 64

Neuronal computation requires a combination of at least three kinds of K+ channels. What three channels are involved?

Answer 64

K+ channels (located in intial segment): **delayed**, **rapidly inactivating**, and **Ca2+-activated K+ channels**.

Question 65

Neuronal computation requires a combination of at least three kinds of K+ channels. One reason for mult types of channels is bc v-gated Na+ channels alone are insufficent to carry out repetitive firing of APs. Explain why.

Answer 65

**Issue: repetitive firing; v-gated Na+ channels alone are insufficient**: * When depol threshold of axon hillock is crossed → Na+ channels open → AP → AP terminated by inactivation of Na+ channels. * **Before another AP could fire, Na+ channels would have to recover fr inactivation, wh would not occur as long as strong depol stim (fr PSPs) persisted; thus, additional type(s) of channels**—partic **delayed K+ channels**—req'd to **repolarize** mem after ea AP. * **Delayed K+ channels** - v-gated, slower kinetics → open only during falling phase of AP (Na+ channels inactive). * …AP fired → AP terminated by inactivation of Na+ channels… * **Delayed K+ channels open → efflux of K+ → mem repols back toward K+ equil pot (v neg) → Na+ channels rapidly recover fr inactivated state & closes delayed K+ channels → axon hillock ready for next AP**. * Thus, sustained stim of dendrites/cell body → repetitive AP firing.

Question 66

Neuronal computation requires a combination of at least three kinds of K+ channels. One reason for mult types of channels is bc the combo of v-gated Na+ channels and delayed K+ channels (wh permit repetitive firing) is insufficent in transmitting the proper frequency of firing to reflect stim intensity. Explain why.

Answer 66

**Issue: frequency of firing must reflect stim intensity; combo of Na+/delayed K+ channels is insufficient**. * *Steady* stim below threshold → no AP. * Above threshold → APs abruptly fired at relatively rapid rate; **solved w rapidly inactivating K+ channels**: * **Rapidly inactivating K+ channels** - v-gated; open when mem depols, but specific voltage sensitivity/kinetics of inactivation reduce rate of firing at levels of stim only just above threshold. * **Removes discontinuity in relationship b/w firing rate/stim intensity → firing rate *proportional* to strength of depol stim over v broad range**.

Question 67

Describe how v-gated Ca2+ channels and Ca2+-activated K+ channels work t/g to ↓ response of cell to a constant, prolonged stim; "adaptation".

Answer 67

* **Ca2+ channels**: similar to Ca2+ channels that mediate release of nxmtr fr presyn axon terminals; open when AP fires → transient influx of Ca2+ into axon hillock. * **Ca2+-activated K+ channels**: open in response to ↑ [Ca2+] at channel’s cytoplasmic face. * Prolonged, strong depol stimuli → long train of APs → ea AP permits brief influx of Ca2+ thru **v-gated Ca2+ channels** → local cytosolic [Ca2+] gradually ↑ → **Ca2+-activated K+ channels** open → **↑ delay b/w APs**. * Recall: K+ channels open → mem-pot moves toward v neg K+ equil pot, i.e. inhibitory (harder to depol). * Thus, constant, prolonged stim → neuron gradually less responsive (adaptation).

Question 68

Long-term potentiation (LTP) in mammalian hippocampus deps on ____ entry thru \_\_\_\_\_-receptor channels.

Answer 68

Long-term potentiation (LTP) in mammalian hippocampus deps on **Ca2+** entry thru **NMDA**-receptor channels. * **NMDA-receptor channels** - special role in some forms of synaptic plasticity (altering strength dep on usage; i.e. learning/memory); located at many excitatory synapses in CNS; gated by both voltage and glutamate (excitatory nxmtr).

Question 69

The hippocampus plays a special role in learning in that it displays a striking form of synaptic plasticity w repeated use. Describe how LTP is established.

Answer 69

Occasional single APs in presyn cells leave no lasting trace, but a short burst of repetitive firing causes **LTP** → subseq single APs evoke signif enhanced response in postsyn cells. * Effect lasts hours/days/weeks, dep on #/intensity of bursts of repetitive firing. * Only activated synapses exhibit LTP; uninvolved synapses on same postsyn cell remain unaffected. * H/e, while cell is receiving burst of repetitive stim via one set of synapses, if a single AP is delivered at another synapse on its surface → latter synapse will also undergo LTP. * Thus, **LTP occurs on any occasion when a presyn cell fires (once or more) at a time when the postsyn mem is strongly depol'd (either thru recent repetitive firing of same presynaptic cell or by other means)**.

Question 70

Glutamate-gated ion channels are the most common of all xmtr-gated channels in brain; incl two subclasses: AMPA-receptors, wh carry most of depol current resp for ePSPs (typ mechanism of operation), and NMDA-receptors, wh are doubly gated and are selectively activated by artifical glutamate analog N-methyl-D-aspartate (hence, NMDA). Describe how NMDA receptors are involved in learning/memory formation.

Answer 70

* **NMDA-receptors o**pen only when *two conditions* satisfied simult: glutamate bound to receptor, and mem must be strongly depold. * Strong depol → releases Mg2+, wh normally block resting channel; i.e. **normally activated only when AMPA receptors are activated (cause mem depol).** * **Critical for LTP**: if selectively blocked (via specific inhibitor or inactivated genetically) → LTP does not occur → specific deficits in learning abilities, but behave almost normally otherwise. * NMDA-receptor channels open → highly permeable to Ca2+, wh acts as an IC signal in postsyn cell → triggers cascade of changes resp for LTP. * Can inject Ca2+ chelator EGTA into postsyn cell → Ca2+ levels held artificially low → LTP prevented. * Likewise, can artificially raise IC [Ca2+] in postsyn cell → induce LTP; e.g. insert new AMPA receptors into postsyn cell pmem. * Some cases, can also induce LTP via changes to presyn cell, e.g. to release more glutamate.

Question 71

Acetylcholine is made in the cytosol and then transported into synaptic vesicles, where its concentration is more than 100-fold higher than in the cytosol. When synaptic vesicles are isolated from neurons, they can take up additional acetylcholine added to the solution in which they are suspended, but only when ATp is present. na+ ions are not required for the uptake, but, curiously, raising the ph of the solution in which the synaptic vesicles are suspended increases the rate of uptake. Furthermore, transport is inhibited when drugs are added that make the membrane permeable to h+ ions. suggest a mechanism that is consistent with all of these observations.

Answer 71

Acetylcholine is being transported into the vesicles by an H+–acetylcholine antiport in the vesicle membrane. The H+ gradient that drives the uptake is generated by an ATP-driven H+ pump in the vesicle membrane, which pumps H+ into the vesicle (hence the dependence of the reaction on ATP). Raising the pH of the solution surrounding the vesicles decreases the H+ concentration of the solution, thereby increasing the outward gradient across the vesicle membrane, explaining the enhanced rate of acetylcholine uptake.

Question 72

Endosomes need an acidic lumen in order to function. Acidifcation is achieved by an H+ pump in the endosomal mem, wh also contains Cl– channels. If the channels do not function properly (e.g. bc of a mutation in the genes encoding the channel proteins), acidifcation is also impaired. A. Explain how Cl– channels might help acidifcation? B. According to your explanation, would the Cl– channels be absolutely req'd to ↓ pH inside endosome?

Answer 72

A. If H+ is pumped across the membrane into the endosomes, an electrochemical gradient of H+ results— composed of both an H+ concentration gradient and a membrane potential, with the interior of the vesicle positive. Both of these components add to the energy that is stored in the gradient and that must be supplied to generate it. The electrochemical gradient will limit the transfer of more H+. If, however, the membrane also contains Cl– channels, the negatively charged Cl– in the cytosol will flow into the endosomes and diminish their membrane potential. It therefore becomes energetically less expensive to pump more H+ across the membrane, and the interior of the endosomes can become more acidic. B. No. As explained in (A), some acidifcation would still occur in their absence.

Question 73

Acetylcholine-gated cation channels do not discriminate between na+, K+, and ca2+ ions, allowing all to pass through them freely. so why is it that when acetylcholine binds to this protein in the plasma membrane of muscle cells, the channel opens and there is a large net infux of primarily na+ ions?

Answer 73

The membrane potential and the steep extracellular Na+ concentration provide a large inward electrochemical driving force and a large reservoir of Na+ ions, so that mostly Na+ ions enter the cell as acetylcholine receptors open. Ca2+ ions will also enter the cell, but their infux is much more limited because of their lower extracellular concentration. (Most of the Ca2+ that enters the cytosol to stimulate muscle contraction is released from intracellular stores). Bc of high IC [K+] and the opposing direction of the membrane potential, there will be little if any movement of K+ ions upon opening of a cation channel.