---start physio 1.13.97

smooth muscle
dr kotlikoff
8-2839
mik@pobox.upenn.edu

handout: smooth muscle excitation-contraction coupling.

When you think of smooth muscle and its functions can you think of a 
fundamental difference or different job it has to do vis a vis 
cardiac/skeletal muscle? it undergoes SUSTAINED contraction. eg, vascular 
smooth muscle is always on, always contracted. you don't relax it 
completely, or you will become hypotensive and fall over and die. so it 
serves a tonic function. also, it does a diverse number of jobs, it has 
to regulate pupillary dimension and vascular tone, it has to regulate GI 
tone, peristalsis, bladder tone, airway tone, etc. so the muscle tissue 
is diverse and the regulation is diverse. as we go through the regulatory 
mechanisms by which the smooth muscle contracts and relaxes we'll see the 
diversity.

smooth muscle is in every organ, because every organ is perfused.some 
organs are mostly smooth muscle: bladder, iris, etc, where organ function 
is totally dependent on it. also kidney, because regulation of blood flow 
through kidney is vital eg function is regulated via regulation of 
perfusion.

so.

let's start with structure and cell biology.
smooth muscle cells are secretory cells. they secrete a collagen matrix, 
sometimes also elastin. they are actively synthetic, continually 
secreting these proteins at all times, if they stop, can lead to 
pathology. also they are dividing cells unlike striated muscle cells. 
striated muscle cells are terminally differentiated tubular structures. 
smooth muscle cells can divide and proliferate and become hyperplastic 
-important component of pathology of asthma (thickened airway muscle 
layer), hypertension, etc. stimuli leading to constriction of sm muscle 
may be associated w/increased cell proliferation.
also, an extensive sarcoplasmic reticulum SR exists beneath plasma 
membrane. unlke T tubular system of striated muscles, there is no obvious 
junction between plasma membrane and SR. sm musc is more disorganized. it 
has randomly placed SR just under membrane and throughout cytosol. also 
has irregular pattern of contractile proteins which cause strange bulging 
when cell contracts.

how is this muscle controlled?

-NEURAL control: autonomic NS. it's mostly involuntary. recall the motor 
unit of skeletal muscle: one nerve ending per motor unit. very finely 
controlled. but SMOOTH muscle is different. one nerve can touch many 
cells. one cell can have input from multiple nerves.  a descending 
autonomic nerve releases ACH or NOREPI at cell, resulting in contractile 
stimulus (causes postsynaptic potential).  so neural control is diverse 
and of two types
--few inputs to muscle: muscle kind of a syncitium of cells, and 
contracts as one unit. or, multi-unit: more like skeletal muscle: areas 
of the muscle contract together. see handout. dense innervation == 
multiunit; sparse innervation==single unit.
smooth musc cells have high input resistance and good elec coupling so 
conducts signals well and minimal neural input easily spreads, allowing 
area to act as syncitium.

in certain organs there is also local integration at level of synapse, 
local ganglia. so if there is synaptic input close to muscle organ and 
short postganglionic fiber you may get signal integration causing 
contraction or not...this can be important in the gut so it can act w/o 
descending input.

indirect control: eg in vessel. neural input to endothelium: ACH 
released, causes NO to be released by endothelium, causes local 
vasodilation

HORMONAL control (says HUMORAL) on the board: vessels respond to 
circulating catecholamines, airways respond to andrenergics, there are 
shifts in sm muscle contraction based on release of EPI during stress (a 
humoral release mechanism).

LOCAL pathways: if there is constriction of a vessel and there isn't 
enough blood flow, a buildup of local products will feed back and relax 
the vessel.


ELECTRICAL BEHAVIOR: Excitation contraction coupling. very important. p 4 
of handout. see fig 5 top left. there are cells which have APs and the 
contraction is a function of the frequency of firing of the muscle. the 
more APs, the more tension you'll get in the organ. also in the gut, slow 
waves are generated by rhythmic pacemakers in the tissue, with spike 
waves on top of that. see fig c. you also have tissue where you have 
graded depolarization, and tissue will contract when depolarized and 
relax when hyperpolarized. this is a tonic tissue, because there is no 
spike but rather only graded polarization - tone varies w/membrane 
potential. how do tissues contract in absence of depolarization? (fig d) 
usually based on calcium - voltage gated ca++ channels often mediate the 
action potential and will turn on, causing increased intracellular ca++ 
and contraction of cell. so you have AP, ca++ channel opens, etc. inside 
a cell, ca++ concentration is so low that any change is very obvious. 
with sodium, opening a channel doesn't affect concentration much because 
the concentration isn't that different inside th cell. but ca++ it's an 
order of magnitude.

smooth muscle contractions are slower in onset and longer in duration. sm 
muscle always has some tone, doesn't totally turn off.

second major source of ca++ in sm musc is the SR. it will release Ca++ 
when a neurotransmitter is bound, via the IP3 pathway. a 7 domain 
transmembrane receptor is activated, yada yada see handout. IP3 binds to 
receptors on SR and Ca++ floods out. this is a bigger source of ca++ than 
the voltage gated channels. then it's taken back up into SR.

also there are ryanodine receptors which mediate ca++induced ca++ 
release. this is more important in cardiac muscle. these receptors bind 
calcium and promote more ca++ release =- see handout. may be important in 
bladder, probably not everywhere else. caffeine binds thse receptors.

see fig 7 p 5 hormone binds receptor, activates phoslip C, IP3, binds SR 
recep, releases Ca++

third mechanism to keep in mind: cation channels found in sm muscle, some 
ca++permeable, not all. several families of these channels found 
recently. one on p 6 of handout (don't need to know details) P2x receptor 
binds ATP and allows Na+ and Ca++ to pass through. it stays open longer 
than Ca++channel.

Ca++ atp ases: these are pumps that get calcium back OUT of the cell.
pumps are slower than channels, work against the gradient unlike 
channels, require ATP to cycle unlike channels.  so these are ATP driven 
pumps that transpose Ca++ into ECF and SR. there are differencs between 
the SR pump and membrane pump. the SR pump is also able to be 
phosphorylated and actively regulated. hormone binds, activates cAMP, 
activates kinases, etc.

P 7, see fig 10. 
A. receptor activated ion channels can be activated by neurotransmitter 
etc, allowing ca++influx

B. Ca++ channel, voltage gated

C. release of Ca from SR by IP3

D Ca++ ATPase in membrane and SR.

--

all of the above can be regulated. the receptor g protein can be 
regulated, whatever.

So there are those ways of Ca++ influx...release of intracellular Ca++ 
stores, and modulation of Ca++ sensitivity of contractile proteins.

possibly increased myosin phosphorylation occurs at a given Ca++ level 
due to agonist dependent inhibition of myosin phosphatase so at any given 
level of MLCK activity, greater myosin phosphorylation and tension would 
result. system is intrinsically off and has to be turned on. these 
processes are heavily regulated by phosphorylation mechanisms. if you 
regulate the myosin phosphatase, you can keep the myosin phosphorylated 
longer, causing increased lenght of contraction under constant ca++level.

(he won't ask us about that though)

RELAXATION
in skeletal muscle, relaxation == lack of neural input. same w/heart: if 
no vagal AP, no heartbeat.

in sm muscle, relaxation is more an active process.
net level of contraction dependent on net integration of excitatory and 
inhibitory input.

-Modulation of ICF Ca++ level: decrease in Ca++ in the cell - can 
regulate the Ca++ ATPase, can modulate cAMP level, can open ion channels 
(K+) which will hyperpolarize the cell (these respond to relaxing 
receptor input)

there are 4 kinds of K+ channels important in regulating tone

Ca++ activated: when Ca++ rises in the cell, they open - negative 
feedback.

delayed rectifier K+ channels also seen in cardiac muscle

ATP sensitive K+ channels also important in heart - when ATP level falls, 
they open.

inwardly rectifying K+ channels-important mechanism for hyperpolarizing 
sm musc.

see p 10- summary

skeletal							smooth
single motor unit					no motor unit
all cells in unit contract			diffuse response
single nerve/cell;			  one axon innervates many cells;multiple axons/cel
single channel (nicotinic)			many channels mediate depolarization 
single Ca++ source: SR				extra and intracellular Ca++ sources
cal release coupled to depolarization   ca++ released via IP3 pathway
direct mode of ca action			indirect effect of ca on MLCK
relaxation: no neural input			see above :) many mechanisms

control of sm muscle very diverse as described above. can be finely tuned 
like iris or more general like the gut which acts largely on its own and 
as syncitium. local control due to release of metabolites, buildup in 
region.

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